Pyrazolopyridine Derivatives and Uses thereof

ABSTRACT

The present disclosure relates to compounds of formula (I) and pharmaceutical compositions and their use in reducing Widely Interspaced Zinc Finger Motifs (WIZ) expression levels, or inducing fetal hemoglobin (HbF) expression, and in the treatment of inherited blood disorders (e.g., hemoglobinopathies, e.g., beta-hemoglobinopathies), such as sickle cell disease and beta-thalassemia.

CLAIM OF PRIORITY

This application claims the benefit of priority to U.S. ProvisionalApplication No. 63/161,139 filed Mar. 15, 2021, and U.S. ProvisionalApplication No. 63/164,130 filed Mar. 22, 2021, the disclosures of whichare incorporated by reference herein in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jul. 16, 2021 isnamed PAT069039-US-PSP02_SL.txt and is 4,096 bytes in size.

FIELD OF THE DISCLOSURE

The present disclosure relates to pyrazolopyridine derivatives compoundsand pharmaceutical compositions and their use in reducing WidelyInterspaced Zinc Finger Motifs (WIZ) protein expression levels and/orinducing fetal hemoglobin (HbF) protein expression levels, and in thetreatment of inherited blood disorders (hemoglobinopathies, e.g.,beta-hemoglobinopathies), such as sickle cell disease andbeta-thalassemia.

BACKGROUND OF THE DISCLOSURE

Sickle cell disease (SCD) is a group of severe inherited blood disordersthat cause red blood cells to contort into a sickle shape. These cellscan cause blockages in blood flow, leading to intense pain, organ damageand premature death. Beta thalassemias are a group of inherited blooddisorders that are caused by reduced or absent synthesis of beta globin,causing anemia.

Fetal hemoglobin (HbF) induction is known to ameliorate symptoms in SCDand beta-thalassemia patients, with both genetic (single nucleotidepolymorphisms in the globin control locus & BCL11A) and pharmacologic(hydroxyurea) validation in the clinic (Vinjamur, D. S., et al. (2018),The British Journal of Haematology, 180(5), 630-643). Hydroxyurea is thecurrent standard of care for SCD and is thought to provide benefit viainduction of HbF, but is genotoxic, causes dose-limiting neutropenia andhas a response rate of less than 40%. Other mechanisms being targetedclinically and preclinically include inhibition of HDAC1/2 (Shearstoneet al., 2016, PLoS One, 11(4), e0153767), LSD1 (Rivers et al., 2018,Experimental Hematology, 67, 60-64), DNMT1, PDE9a (McArthur et al.,2019, Haematologica. doi:10.3324/haematol.2018.213462), HRI kinase(Grevet et al., 2018, Science, 361(6399), 285-290) and G9a/GLP (Krivegaet al., 2015, Blood, 126(5), 665-672; Renneville et al., 2015, Blood,126(16), 1930-1939). Additionally, the immunomodulators pomalidomide andlenalidomide induce HbF ex vivo in human primary erythroid cells(Moutouh-de Parseval, L. A. et al. (2008), The Journal of ClinicalInvestigation, 118(1), 248-258) and in vivo (Meiler, S. E. et al.(2011), Blood, 118(4), 1109-1112). WIZ is ubiquitously expressed andplays a role in targeting the G9a/GLP histone methyltransferases togenomic loci to regulate chromatin structure and transcription (Bian,Chen, et al. (2015), eLife 2015; 4:e05606.

SUMMARY OF THE DISCLOSURE

The disclosure relates to a therapeutic agent, which is effective inreducing WIZ protein expression levels and/or inducing fetal hemoglobin(HbF) expression. The disclosure further relates to pyrazolopyridinecompounds, which are effective in reducing WIZ protein expression levelsand/or inducing fetal hemoglobin (HbF) expression, pharmaceuticallyacceptable salts thereof, compositions thereof, and their use intherapies for the conditions and purposes detailed above.

The disclosure provides, in a first aspect, a compound of formula (I″)or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein:

is a single bond or a double bond;

X is selected from CH, CF, and N;

R^(x) is selected from hydrogen, C₁-C₆alkyl, halo (e.g., F, Cl),C₁-C₆alkoxyl, and C₃-C₈cycloalkyl;

R′ is selected from hydrogen and C₁-C₆alkyl;

R¹ is selected from hydrogen and C₁-C₆alkyl;

each R² is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo,and oxo, wherein the C₁-C₆alkyl is substituted with 0-1 occurrence ofR^(2a); or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form a bridgingring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;

R³ is selected from hydrogen, C₁-C₈alkyl, CN₂—C₆alkenyl, —SO₂R⁴,C₁-C₆haloalkyl, —C(═O)—O—(R⁵), —C(═O)—(R⁶), C₃-C₁₀cycloalkyl, and a 4-to 10-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, wherein the C₁-C₈alkyl and C₁-C₆haloalkyl areeach independently substituted with 0-3 occurrences of R^(3a), andwherein the C₃-C₁₀cycloalkyl and 4- to 10-membered heterocyclyl are eachindependently substituted with 0-3 occurrences of R^(3b);

or

R³ together with the nitrogen atom to which it is attached and R²together with the carbon atom to which it is attached form a 5- or6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N, O and S, which 5- or 6-membered heterocyclyl is substituted with0-2 occurrences of an oxo group;

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to10-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, C₆-C₁₀aryl, and —NR^(4b)R^(4c), wherein the C₁-C₆alkyl issubstituted with 0-1 occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R^(4b) is selected from hydrogen, and C₁-C₆alkyl;

R^(4c) is selected from hydrogen, C₁-C₆alkyl, and C₃-C₈cycloalkyl;

R⁵ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl;

R⁶ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, a 4- to10-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, and and —NR^(4b)R^(4c), wherein the C₁-C₆alkylis substituted with 0-1 occurrence of R^(6a), the C₃-C₈cycloalkyl issubstituted with 0-1 occurrence of R^(6b), and the 4- to 10-memberedheterocyclyl is substituted with 0-1 occurrence of C₁-C₆alkyl;

R^(6a) is selected from C₆-C₁₀aryl and C₃-C₈cycloalkyl;

R^(6b) is selected from halo, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, andC₁-C₆alkyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

p is 0 or 1.

The disclosure provides, in a further aspect, a compound of formula (I′)or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein:

is a single bond or a double bond;

X is selected from CH, CF, and N;

R′ is selected from hydrogen and C₁-C₆alkyl;

R¹ is selected from hydrogen and C₁-C₆alkyl;

each R² is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo,and oxo, wherein the C₁-C₆alkyl is substituted with 0-1 occurrence ofR^(2a); or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form a bridgingring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;

R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴,C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and —C(═O)—(R⁶), wherein the C₁-C₈alkyland C₁-C₆haloalkyl are independently substituted with 0-3 occurrences ofR^(3a);

or

R³ together with the nitrogen atom to which it is attached and R²together with the carbon atom to which it is attached form a 5- or6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N, O and S;

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R⁵ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl;

R⁶ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, whereinthe C₁-C₆alkyl is substituted with 0-1 occurrence of R^(6a) and theC₃-C₈cycloalkyl is substituted with 0-1 occurrence of R^(6b);

R^(6a) is selected from C₆-C₁₀aryl and C₃-C₈cycloalkyl;

R^(6b) is selected from halo, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, andC₁-C₆alkyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

p is 0 or 1.

The disclosure provides, in a further aspect, a compound of formula (I)or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein:

X is selected from CH, CF, and N;

R′ is selected from hydrogen and C₁-C₆alkyl;

R¹ is selected from hydrogen and C₁-C₆alkyl;

each R² is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo,and oxo, wherein the C₁-C₆alkyl is substituted with 0-1 occurrence ofR^(2a); or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form a bridgingring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;

R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴,C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and —C(═O)—(R⁶), wherein the C₁-C₈alkyland C₁-C₆haloalkyl are independently substituted with 0-3 occurrences ofR^(3a);

or

R³ together with the nitrogen atom to which it is attached and R²together with the carbon atom to which it is attached form a 5- or6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N, O and S;

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R⁵ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl;

R⁶ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, whereinthe C₁-C₆alkyl is substituted with 0-1 occurrence of R^(6a) and theC₃-C₈cycloalkyl is substituted with 0-1 occurrence of R^(6b);

R^(6a) is selected from C₆-C₁₀aryl and C₃-C₈cycloalkyl;

R^(6b) is selected from halo, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, andC₁-C₆alkyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

p is 0 or 1.

In a further aspect, the disclosure provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib),(Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″),(Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, and a pharmaceuticallyacceptable carrier or excipient.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use as a medicament.

In a further aspect, the disclosure provides a method of treating orpreventing a disease or disorder in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′),(Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id),(Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In a further aspect, the disclosure provides a method of treating orpreventing a disorder that is affected by the reduction or modulation ofWIZ protein levels, in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In a further aspect, the disclosure provides a method of inhibiting WIZprotein expression in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In a further aspect, the disclosure provides a method of degrading WIZprotein in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In an further aspect, the disclosure provides a method of inhibiting,reducing, or eliminating the activity of WIZ protein or WIZ proteinexpression, the method comprising administering to the subject acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In a further aspect, the disclosure provides a method of inducing orpromoting fetal hemoglobin in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia),(Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1),(Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In a further aspect, the disclosure provides a method of reactivatingfetal hemoglobin production or expression in a subject in need thereof,the method comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′),(Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id),(Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In an further aspect, the disclosure provides a method of increasingfetal hemoglobin expression in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia),(Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1),(Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In a further aspect, the disclosure provides a method of treating ahemoglobinopathy, e.g., a beta-hemoglobinopathy, in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a compound of formula (I″), (I′),(I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″),(Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

In a further aspect, the disclosure provides a method of treating asickle cell disease in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In a further aspect, the disclosure provides a method of treatingbeta-thalassemia in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder.

In a further aspect, the disclosure provides a compound of (I″), (I′),(I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″),(Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder selected from sickle cell disease and beta-thalassemia.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment orprevention of a disease or disorder that is affected by the reduction ofWIZ protein levels.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment orprevention of a disease or disorder that is affected by the inhibitionor reduction of WIZ protein expression.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment orprevention of a disease or disorder that is affected by the degradationof WIZ protein.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in inhibiting, reducing, oreliminating the activity of WIZ protein or WIZ protein expression.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in inducing or promotingfetal hemoglobin.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in reactivating fetalhemoglobin production or expression.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in increasing fetalhemoglobin expression.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of ahemoglobinopathy.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a sicklecell disease.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment ofbeta-thalassemia.

In a further aspect, the disclosure provides a compound of (I″), (I′),(I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″),(Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder affected by an increase in fetal hemoglobin expression.

In a further aspect, the disclosure provides a compound of (I″), (I′),(I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″),(Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder affected by the inhibition, reduction, or elimination of theactivity of WIZ protein or WIZ protein expression.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder affected by the induction or promotion of fetal hemoglobin.

In a further aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder affected by the reactivation of fetal hemoglobin productionor expression.

Various other aspects of the disclosure are described herein and in theclaims.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. In the specification andclaims, the singular forms also include the plural unless the contextclearly dictates otherwise. Although methods and materials similar orequivalent to those described herein can be used in the practice ortesting of the disclosure, suitable methods and materials are describedbelow. All publications, patent applications, patents, and otherreferences mentioned herein are incorporated by reference in theirentireties for all purposes. The references cited herein are notadmitted to be prior art to the claimed disclosure. In the case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting.

Other features and advantages of compounds, compositions, and methodsdisclosed herein will be apparent from the following detaileddescription and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A depicts a volcano plot of differentially expressed genes fromWIZ KO cells as compared to a scrambled gRNA control. Each dotrepresents a gene. HBG1/2 genes are differentially upregulated withWIZ_6 and WIZ_18 gRNA targeting WIZ KO.

FIG. 1B depicts a bar graph showing the frequency of HbF+ cells due toshRNA− mediated loss of WIZ in human mobilized peripheral blood CD34+derived erythroid cells.

FIG. 1C depicts a bar graph showing the frequency of HbF+ cells due toCRISPR/Cas9-mediated loss of WIZ in human mobilized peripheral bloodCD34+ derived erythroid cells.

DETAILED DESCRIPTION OF THE DISCLOSURE

The compounds disclosed herein are effective in reducing WIZ proteinexpression levels, or inducing fetal hemoglobin (HbF) expression.Without wishing to be bound by any theory, it is believed that thedisclosed compounds may treat blood disorders, such as inherited blooddisorders, e.g., sickle cell disease, and beta-thalassemia by inducingfetal hemoglobin HbF expression.

Definitions

Unless specified otherwise, the terms “compounds of the presentdisclosure,” “compounds of the disclosure,” or “compound of thedisclosure” refer to compounds of formulae (I″), (I′), (I), (Ia″),(Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id),(Id-1), (Id-2), (Id-3), (Ie″), (Ie′), and (Ie), exemplified compounds,salts thereof, particularly pharmaceutically acceptable salts thereof,hydrates, solvates, prodrugs, as well as all stereoisomers (includingdiastereoisomers and enantiomers), rotamers, tautomers, and isotopicallylabeled compounds (including deuterium substitutions), as well asinherently formed moieties.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁-C₈alkylmeans an alkyl group or radical having 1 to 8 carbon atoms. In general,for groups comprising two or more subgroups, the last named group is theradical attachment point, for example, “alkylaryl” means a monovalentradical of the formula alkyl-aryl-, while “arylalkyl” means a monovalentradical of the formula aryl-alkyl-.

Furthermore, the use of a term designating a monovalent radical where adivalent radical is appropriate shall be construed to designate therespective divalent radical and vice versa. Unless otherwise specified,conventional definitions of terms control and conventional stable atomvalences are presumed and achieved in all formulas and groups. Thearticles “a” and “an” refer to one or more than one (e.g., to at leastone) of the grammatical object of the article. By way of example, “anelement” means one element or more than one element.

The term “and/or” means either “and” or “or” unless indicated otherwise.

The term “substituted” means that the specified group or moiety bearsone or more suitable substituents wherein the substituents may connectto the specified group or moiety at one or more positions. For example,an aryl substituted with a cycloalkyl may indicate that the cycloalkylconnects to one atom of the aryl with a bond or by fusing with the aryland sharing two or more common atoms.

As used herein the term “C₁-C₈alkyl” refers to a straight or branchedhydrocarbon chain radical consisting solely of carbon and hydrogenatoms, containing no unsaturation, having from one to eight carbonatoms, and which is attached to the rest of the molecule by a singlebond.

The terms “C₁-C₃alkyl”, “C₁-C₄alkyl”, “C₁-C₆alkyl”, are to be construedaccordingly. Examples of C₁-C₈alkyl include, but are not limited to,methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl,1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl or i-butyl),1,1-dimethylethyl (t-butyl), n-pentyl, 3-pentyl, n-hexyl, n-heptyl,4-heptyl, n-octyl, 2-isopropyl-3-methylbutyl.

As used herein, the term “C₁-C₆alkoxyl” refers to a radical of theformula —OR_(a) where R_(a) is a C₁-C₆alkyl radical as generally definedabove. Examples of C₁-C₆alkoxyl include, but are not limited to,methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, tert-butoxy,sec-butoxy, pentoxy, and hexoxy.

As used herein, the term “C₁-C₆haloalkyl” refers to C₁-C₆alkyl radical,as defined above, substituted by one or more halo radicals, as definedherein. Examples of C₁-C₆haloalkyl include, but are not limited to,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-fluoropropyl, 1,1,1-trifluoropropyl, 2,2-difluoropropyl,3,3-difluoropropyl and 1-fluoromethyl-2-fluoroethyl,1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl,1,1,2,2-tetrafluoropropyl, and 1,4,4-trifluorobutan-2-yl.

As used herein, the term “C₁-C₆haloalkoxyl” means a C₁-C₆alkoxyl groupas defined herein substituted with one or more halo radicals. Examplesof C₁-C₆haloalkoxyl groups include, but are not limited to,trifluoromethoxy, difluoromethoxy, fluoromethoxy, trichloromethoxy,1,1-difluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy,1-fluoromethyl-2-fluoroethoxy, pentafluoroethoxy, 2-fluoropropoxy,3,3-difluoropropoxy and 3-dibromopropoxy. Preferably, the one or morehalo radicals of C₁-C₆haloalkoxyl is fluoro. Preferably,C₁-C₆haloalkoxyl is selected from trifluoromethoxy, difluoromethoxy,fluoromethoxy, 1,1-difluoroethoxy, 2,2-difluoroethoxy,2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, andpentafluoroethoxy.

The term “halogen” or “halo” means fluoro, chloro, bromo or iodo.

As used herein, the term “cycloalkyl” means a monocyclic or polycyclicsaturated or partially unsaturated carbon ring containing 3-18 carbonatoms wherein there are no delocalized pi electrons (aromaticity) sharedamong the ring carbon. The terms “C₃-C₁₀cycloalkyl”, “C₃-C₈cycloalkyl”,“C₄-C₁₀cycloalkyl” and “C₄-C₇cycloalkyl” are to be construedaccordingly. The term polycyclic encompasses bridged (e.g., norbonane),fused (e.g., decalin) and spirocyclic cycloalkyl. Preferably,cycloalkyl, e.g., C₃-C₁₀cycloalkyl, is a monocyclic, bridged orspirocyclic hydrocarbon group of 3 to 10 carbon atoms.

Examples of cycloalkyl groups include, without limitations,cyclopropenyl, cyclopropyl cyclobutyl, cyclobutenyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,spiro[3.3]heptanyl (e.g., spiro[3.3]heptan-6-yl), bicyclo[2.2.2]octanyl,bicyclo[2.2.2]octenyl, adamantyl and derivatives thereof. Preferably,the cycloalkyl group is saturated.

Preferred examples of C₃-C₁₀cycloalkyl include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl(e.g., spiro[3.3]heptan-6-yl), bicyclo[1.1.1]pentyl,bicyclo[2.1.1]hexyl, bicyclo[2.1.1]heptyl, bicyclo[2.2.2]octyl andadamantyl.

“Heterocyclyl” means a saturated or partially saturated monocyclic orpolycyclic ring containing carbon and at least one heteroatom selectedfrom oxygen, nitrogen, and sulfur (0, N, and S) and wherein there are nodelocalized pi electrons (aromaticity) shared among the ring carbon orheteroatoms. The terms “4- to 10-membered heterocyclyl”, “4- to6-membered heterocyclyl” and “5- or 6-membered heterocyclyl” are to beconstrued accordingly. The heterocyclyl ring structure may besubstituted by one or more substituents. The substituents can themselvesbe optionally substituted. The heterocyclyl may be bonded via a carbonatom or heteroatom. The term polycyclic encompasses bridged, fused andspirocyclic heterocyclyl.

Examples of heterocyclyl rings include, but are not limited to,oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, oxazolidinyl, thiazolidinyl,pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl,morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinylS-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl,oxazolidinonyl, 1,4-dioxanyl, dihydrofuranyl, 1,3-dioxolanyl,imidazolidinyl, dihydroisoxazolinyl, pyrrolinyl, pyrazolinyl,oxazepinyl, dithiolanyl, homotropanyl, dihydropyranyl (e.g.,3,6-dihydro-2H-pyranyl), oxaspiroheptanyl (e.g.,2-oxaspiro[3.3]heptan-6-yl), diazabicyclo[3.2.1]octan-3-yl),2-azaspiro[3.3]heptanyl (e.g., 2-azaspiro[3.3]heptan-6-yl), and thelike.

Preferred examples of heterocyclyl include, without limitations,oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, piperazinyl, dihydroisoxazolinyl,tetrahydropyranyl, morpholinyl, dihydropyranyl (e.g.,3,6-dihydro-2H-pyranyl) 2-azaspiro[3.3]heptanyl (e.g.,2-azaspiro[3.3]heptan-6-yl) and oxaspiroheptanyl (e.g.,2-oxaspiro[3.3]heptan-6-yl).

As used herein, the term “aryl” as used herein means monocyclic,bicyclic or polycyclic carbocyclic aromatic rings. Examples of arylinclude, but are not limited to, phenyl, naphthyl (e.g., naphth-1-yl,naphth-2-yl), anthryl (e.g., anthr-1-yl, anthr-9-yl), phenanthryl (e.g.,phenanthr-1-yl, phenanthr-9-yl), and the like. Aryl is also intended toinclude monocyclic, bicyclic or polycyclic carbocyclic aromatic ringssubstituted with carbocyclic aromatic rings. Representative examples arebiphenyl (e.g., biphenyl-2-yl, biphenyl-3-yl, biphenyl-4-yl),phenylnaphthyl (e.g., 1-phenylnaphth-2-yl, 2-phenylnaphth-1-yl), and thelike. Aryl is also intended to include partially saturated bicyclic orpolycyclic carbocyclic rings with at least one unsaturated moiety (e.g.,a benzo moiety). Representative examples are, indanyl (e.g., indan-1-yl,indan-5-yl), indenyl (e.g., inden-1-yl, inden-5-yl),1,2,3,4-tetrahydronaphthyl (e.g., 1,2,3,4-tetrahydronaphth-1-yl,1,2,3,4-tetrahydronaphth-2-yl, 1,2,3,4-tetrahydronaphth-6-yl),1,2-dihydronaphthyl (e.g., 1,2-dihydronaphth-1-yl,1,2-dihydronaphth-4-yl, 1,2-dihydronaphth-6-yl), fluorenyl (e.g.,fluoren-1-yl, fluoren-4-yl, fluoren-9-yl), and the like. Aryl is alsointended to include partially saturated bicyclic or polycycliccarbocyclic aromatic rings containing one or two bridges. Representativeexamples are, benzonorbornyl (e.g., benzonorborn-3-yl,benzonorborn-6-yl), 1,4-ethano-1,2,3,4-tetrahydronapthyl (e.g.,1,4-ethano-1,2,3,4-tetrahydronapth-2-yl,1,4-ethano-1,2,3,4-tetrahydronapth-10-yl), and the like. The term“C₆-C₁₀aryl” is to be construed accordingly.

Preferred examples of aryl include, but are not limited to, indenyl,(e.g., inden-1-yl, inden-5-yl) phenyl (C₆H₅), naphthyl (C₁₀H₇) (e.g.,naphth-1-yl, naphth-2-yl), indanyl (e.g., indan-1-yl, indan-5-yl), andtetrahydronaphthalenyl (e.g., 1,2,3,4-tetrahydronaphthalenyl).

Preferably, C₆-C₁₀aryl refers to a monocyclic or bicyclic carbocyclicaromatic ring.

Preferred examples of C₆-C₁₀aryl include, but are not limited to, phenyland naphthyl. In an embodiment, C₆-C₁₀aryl is phenyl.

As used herein, the term “heteroaryl” as used herein is intended toinclude monocyclic heterocyclic aromatic rings containing one or moreheteroatoms selected from oxygen, nitrogen, and sulfur (O, N, and S).Representative examples are pyrrolyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyrazolyl, isothiazolyl, isooxazolyl, triazolyl,(e.g., 1,2,4-triazolyl), oxadiazolyl, (e.g., 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl(e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl), tetrazolyl, pyranyl, pyridinyl, pyridazinyl,pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, thiadiazinyl, azepinyl, azecinyl, and the like.

Heteroaryl is also intended to include bicyclic heterocyclic aromaticrings containing one or more heteroatoms selected from oxygen, nitrogen,and sulfur (O, N, and S). Representative examples are indolyl,isoindolyl, benzofuranyl, benzothiophenyl, indazolyl, benzopyranyl,benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl,benzisoxazolyl, benzoxazinyl, benzotriazolyl, naphthyridinyl,phthalazinyl, pteridinyl, purinyl, quinazolinyl, cinnolinyl, quinolinyl,isoquinolinyl, quinoxalinyl, oxazolopyridinyl, isooxazolopyridinyl,pyrrolopyridinyl, furopyridinyl, thienopyridinyl, imidazopyridinyl,imidazopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl,pyrazolotriazinyl, thiazolopyridinyl, thiazolopyrimidinyl,imdazothiazolyl, triazolopyridinyl, triazolopyrimidinyl, and the like.

Heteroaryl is also intended to include polycyclic heterocyclic aromaticrings containing one or more heteroatoms selected from oxygen, nitrogen,and sulfur (O, N, and S). Representative examples are carbazolyl,phenoxazinyl, phenazinyl, acridinyl, phenothiazinyl, carbolinyl,phenanthrolinyl, and the like.

Heteroaryl is also intended to include partially saturated monocyclic,bicyclic or polycyclic heterocyclyls containing one or more heteroatomsselected oxygen, nitrogen, and sulfur (O, N, and S). Representativeexamples are imidazolinyl, indolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, dihydrobenzopyranyl, dihydropyridooxazinyl,dihydrobenzodioxinyl (e.g., 2,3-dihydrobenzo[b][1,4]dioxinyl),benzodioxolyl (e.g., benzo[d][1,3]dioxole), dihydrobenzooxazinyl (e.g.,3,4-dihydro-2H-benzo[b][1,4]oxazine), tetrahydroindazolyl,tetrahydrobenzimidazolyl, tetrahydroimidazo[4,5-c]pyridyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinoxalinyl,and the like.

The heteroaryl ring structure may be substituted by one or moresubstituents. The substituents can themselves be optionally substituted.The heteroaryl ring may be bonded via a carbon atom or heteroatom.

The term “5-10 membered heteroaryl” is to be construed accordingly.

Examples of 5-10 membered heteroaryl include, but are not limited to,indolyl, imidazopyridyl, isoquinolinyl, benzooxazolonyl, pyridinyl,pyrimidinyl, pyridinonyl, benzotriazolyl, pyridazinyl,pyrazolotriazinyl, indazolyl, benzimidazolyl, quinolinyl, triazolyl,(e.g., 1,2,4-triazolyl), pyrazolyl, thiazolyl, oxazolyl, isooxazolyl,pyrrolyl, oxadiazolyl, (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl), imidazolyl, pyrrolopyridinyl,tetrahydroindazolyl, quinoxalinyl, thiadiazolyl (e.g.,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl), pyrazinyl, oxazolopyridinyl, pyrazolopyrimidinyl,benzoxazolyl, indolinyl, isooxazolopyridinyl, dihydropyridooxazinyl,tetrazolyl, dihydrobenzodioxinyl (e.g.,2,3-dihydrobenzo[b][1,4]dioxinyl), benzodioxolyl (e.g.,benzo[d][1,3]dioxole) and dihydrobenzooxazinyl (e.g.,3,4-dihydro-2H-benzo[b][1,4]oxazine).

As used herein, the term “oxo” refers to the radical ═O.

“Cyano” or “—CN” means a substituent having a carbon atom joined to anitrogen atom by a triple bond, e.g., C≡N.

The term “C₂-C₆alkenyl” as used herein represents a branched or straighthydrocarbon group having from 2 to 6 carbon atoms and at least onedouble bond. Representative examples are ethenyl (or vinyl), propenyl(e.g., prop-1-enyl, prop-2-enyl), 2-methylprop-1-enyl,2-methylprop-2-enyl, 1,1-(dimethyl)prop-2-enyl, butadienyl (e.g.,buta-1,3-dienyl), butenyl (e.g., but-1-en-1-yl, but-2-en-1-yl),2-methylbut-1-enyl, pentenyl (e.g., pent-1-enyl, pent-2-enyl), hexenyl(e.g., hex-1-enyl, hex-2-enyl, hex-3-enyl), 2-methylpent-3-enyl, and thelike.

As used herein, the term “bridging ring” refers to a ring formed at twonon-adjacent carbon atoms of the heterocycloalkyl moiety of formula (I),linked to form a C₁-C₃ alkylene linker, wherein one of the carbon atomsof said linker is optionally replaced by a heteroatom selected fromnitrogen, oxygen and sulfur. In a preferred embodiment, the alkylenelinker comprises carbon atoms only.

As used herein, the term “C₁-C₃alkylene” refers to a straighthydrocarbon chain bivalent radical consisting solely of carbon andhydrogen atoms, containing no unsaturation, having from one to threecarbon atoms.

As used herein, the term “optionally substituted” includes unsubstitutedor substituted.

As used herein, “

” denotes the point of attachment to the other part of the molecule.

As used herein, the term nitrogen protecting group (PG) in a compound ofFormula (X) or any intermediates in any of the general schemes 1 to 5and subformulae thereof refers to a group that should protect thefunctional groups concerned against unwanted secondary reactions, suchas acylations, etherifications, esterifications, oxidations, solvolysisand similar reactions. It may be removed under deprotection conditions.Depending on the protecting group employed, the skilled person wouldknow how to remove the protecting group to obtain the free amine NH₂group by reference to known procedures. These include reference toorganic chemistry textbooks and literature procedures such as J. F. W.McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, Londonand New York 1973; T. W. Greene and P. G. M. Wuts, “Greene's ProtectiveGroups in Organic Synthesis”, Fourth Edition, Wiley, New York 2007; in“The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), AcademicPress, London and New York 1981; P. J. Kocienski, “Protecting Groups”,Third Edition, Georg Thieme Verlag, Stuttgart and New York 2005; and in“Methoden der organischen Chemie” (Methods of Organic Chemistry), HoubenWeyl, 4th edition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974.

Preferred nitrogen protecting groups generally comprise: C₁-C₆alkyl(e.g., tert-butyl), preferably C₁-C₄alkyl, more preferably C₁-C₂alkyl,most preferably C₁alkyl which is mono-, di- or tri-substituted bytrialkylsilyl-C₁-C₇alkoxy (e.g., trimethylsilyethoxy), aryl, preferablyphenyl, or a heterocyclic group (e.g., benzyl, cumyl, benzhydryl,pyrrolidinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl,(phenyl)methylbenzene) wherein the aryl ring or the heterocyclic groupis unsubstituted or substituted by one or more, e.g., two or three,residues, e.g., selected from the group consisting of C₁-C₇alkyl,hydroxy, C₁-C₇alkoxy (e.g., para-methoxy benzyl (PMB)),C₂-C₈-alkanoyl-oxy, halogen, nitro, cyano, and CF₃,aryl-C₁-C₂-alkoxycarbonyl (preferably phenyl-C₁-C₂-alkoxycarbonyl (e.g.,benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl(POM)), C₁-C₁₀-alkenyloxycarbonyl, C₁-C₆alkylcarbonyl (e.g., acetyl orpivaloyl), C₆-C₁₀-arylcarbonyl; C₁-C₆-alkoxycarbonyl (e.g.,tertbutoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl(Troc), pivaloyl (Piv), allyloxycarbonyl),C₆-C₁₀-arylC₁-C₆-alkoxycarbonyl (e.g., 9-fluorenylmethyloxycarbonyl(Fmoc)), allyl or cinnamyl, sulfonyl or sulfenyl, succinimidyl group,silyl groups (e.g., triarylsilyl, trialkylsilyl, triethylsilyl (TES),trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS),triisopropylsilyl or tertbutyldimethylsilyl).

According to the disclosure, the preferred nitrogen protecting group(PG) can be selected from the group comprising tert-butyloxycarbonyl(Boc), benzyloxycarbonyl (Cbz), para-methoxy benzyl (PMB),2,4-dimethoxybenzyl (DMB), methyloxycarbonyl, trimethylsilylethoxymethyl(SEM) and benzyl. The nitrogen protecting group (PG) is preferably anacid labile protecting group, e.g., tert-butyloxycarbonyl (Boc),2,4-dimethoxybenzyl (DMB).

In some embodiments, the compounds of the disclosure are selective overother proteins.

As used herein, the term “therapeutic agent” in connection with methodsof reducing WIZ protein expression levels and/or inducing fetalhemoglobin (HbF) expression, refers to a substance that results in adetectably lower expression of WIZ gene or WIZ protein or lower activitylevel of WIZ proteins as compared to those levels without suchsubstance.

As used herein “modulator” or “degrader”, means, for example, a compoundof the disclosure, that effectively modulates, decreases, or reduces thelevels of a specific protein (e.g., WIZ) or degrades a specific protein(e.g., WIZ). The amount of a specific protein (e.g., WIZ) degraded canbe measured by comparing the amount of the specific protein (e.g., WIZ)remaining after treatment with a compound of the disclosure as comparedto the initial amount or level of the specific protein (e.g., WIZ)present as measured prior to treatment with a compound of thedisclosure.

As used herein “selective modulator”, “selective degrader”, or“selective compound” means, for example, a compound of the disclosure,that effectively modulates, decreases, or reduces the levels of aspecific protein (e.g., WIZ) or degrades a specific protein (e.g., WIZ)to a greater extent than any other protein. A “selective modulator”,“selective degrader”, or “selective compound” can be identified, forexample, by comparing the ability of a compound to modulate, decrease,or reduce the levels of or to degrade a specific protein (e.g., WIZ) toits ability to modulate, decrease, or reduce the levels of or to degradeother proteins. In some embodiments, the selectivity can be identifiedby measuring the EC₅₀ or IC₅₀ of the compounds. Degradation may beachieved through mediation of an E3 ligase, e.g., E3-ligase complexescomprising the protein Cereblon.

In one embodiment, the specific protein degraded is WIZ protein. In anembodiment, at least about 30% of WIZ is degraded compared to initiallevels. In an embodiment, at least about 40% of WIZ is degraded comparedto initial levels. In an embodiment, at least about 50% of WIZ isdegraded compared to initial levels. In an embodiment, at least about60% of WIZ is degraded compared to initial levels. In an embodiment, atleast about 70% of WIZ is degraded compared to initial levels. In anembodiment, at least about 75% of WIZ is degraded compared to initiallevels. In an embodiment, at least about 80% of WIZ is degraded comparedto initial levels. In an embodiment, at least about 85% of WIZ isdegraded compared to initial levels. In an embodiment, at least about90% of WIZ is degraded compared to initial levels. In an embodiment, atleast about 95% of WIZ is degraded compared to initial levels. In anembodiment, over 95% of WIZ is degraded compared to initial levels. Inan embodiment, at least about 99% of WIZ is degraded compared to initiallevels.

In an embodiment, the WIZ is degraded in an amount of from about 30% toabout 99% compared to initial levels. In an embodiment, the WIZ isdegraded in an amount of from about 40% to about 99% compared to initiallevels. In an embodiment, the WIZ is degraded in an amount of from about50% to about 99% compared to initial levels. In an embodiment, the WIZis degraded in an amount of from about 60% to about 99% compared toinitial levels. In an embodiment, the WIZ is degraded in an amount offrom about 70% to about 99% compared to initial levels. In anembodiment, the WIZ is degraded in an amount of from about 80% to about99% compared to initial levels. In an embodiment, the WIZ is degraded inan amount of from about 90% to about 99% compared to initial levels. Inan embodiment, the WIZ is degraded in an amount of from about 95% toabout 99% compared to initial levels. In an embodiment, the WIZ isdegraded in an amount of from about 90% to about 95% compared to initiallevels.

As used herein, the terms “inducing fetal hemoglobin”, “fetal hemoglobininduction”, or “increasing fetal hemoglobin expression” refer toincreasing the percentage of HbF in the blood of a subject. In anembodiment, the amount of total HbF in the blood of the subjectincreases. In an embodiment, the amount of total hemoglobin in the bloodof the subject increases. In an embodiment, the amount of HbF isincreased by at least about 10%, or at least about 20%, or at leastabout 30%, or at least about 40%, or at least about 50%, or at leastabout 60%, or at least about 70%, or at least about 80%, or at leastabout 90%, or at least about 100%, or more than 100%, for example, atleast about 2-fold, or at least about 3-fold, or at least about 4-fold,or at least about 5-fold, or at least about 6-fold, or at least about7-fold, or at least about 8-fold, or at least about 9-fold, or at leastabout 10-fold, or more than 10-fold as compared to either in the absenceof a compound disclosed herein.

In an embodiment, the total hemoglobin in the blood, e.g., the blood ina subject, is increased by at least about 10%, or at least about 20%, orat least about 30%, or at least about 40%, or at least about 50%, or atleast about 60%, or at least about 70%, or at least about 80%, or atleast about 90%, or at least about 100%, or more than 100%, for example,at least about 2-fold, or at least about 3-fold, or at least about4-fold, or at least about 5-fold, or at least about 6-fold, or at leastabout 7-fold, or at least about 8-fold, or at least about 9-fold, or atleast about 10-fold, or more than 10-fold as compared to either in theabsence of a compound disclosed herein.

The term “a therapeutically effective amount” of a compound of thedisclosure refers to an amount of the compound of the disclosure thatwill elicit the biological or medical response of a subject, forexample, reduction or inhibition of an enzyme or a protein activity, orameliorate symptoms, alleviate conditions, slow or delay diseaseprogression, or prevent a disease, etc. In one embodiment, the term “atherapeutically effective amount” refers to the amount of the compoundof the disclosure that, when administered to a subject, is effective to(1) at least partially alleviate, prevent and/or ameliorate a condition,or a disorder or a disease (i) mediated by WIZ, or (ii) associated withWIZ activity, or (iii) characterized by activity (normal or abnormal) ofWIZ: (2) reduce or inhibit the activity of WIZ; or (3) reduce or inhibitthe expression of WIZ. In another embodiment, the term “atherapeutically effective amount” refers to the amount of the compoundof the disclosure that, when administered to a cell, or a tissue, or anon-cellular biological material, or a medium, is effective to at leastpartially reducing or inhibiting the activity of WIZ; or at leastpartially reducing or inhibiting the expression of WIZ.

“HbF-dependent disease or disorder” means any disease or disorder whichis directly or indirectly affected by the modulation of HbF proteinlevels.

As used herein, the term “subject” refers to primates (e.g., humans,male or female), dogs, rabbits, guinea pigs, pigs, rats and mice. Incertain embodiments, the subject is a primate. In yet other embodiments,the subject is a human.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers to alleviating or ameliorating the disease ordisorder (i.e., slowing or arresting the development of the disease orat least one of the clinical symptoms thereof); or alleviating orameliorating at least one physical parameter or biomarker associatedwith the disease or disorder, including those which may not bediscernible to the patient.

As used herein, the term “prevent”, “preventing” or “prevention” of anydisease or disorder refers to the prophylactic treatment of the diseaseor disorder; or delaying the onset or progression of the disease ordisorder

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the disclosure (especially in the context of the claims) areto be construed to cover both the singular and plural unless otherwiseindicated herein or clearly contradicted by the context.

Various enumerated embodiments of the disclosure are described herein.It will be recognized that features specified in each embodiment may becombined with other specified features to provide further embodiments ofthe disclosure.

Enumerated Embodiments

Embodiment 1. A compound of Formula (I″) or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, wherein:

is a single bond or a double bond;

X is selected from CH, CF, and N;

R^(x) is selected from hydrogen, C₁-C₆alkyl, halo (e.g., F, Cl),C₁-C₆alkoxyl, and C₃-C₈cycloalkyl;

R′ is selected from hydrogen and C₁-C₆alkyl;

R¹ is selected from hydrogen and C₁-C₆alkyl;

each R² is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo,and oxo, wherein the C₁-C₆alkyl is substituted with 0-1 occurrence ofR^(2a); or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form a bridgingring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;

R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴,C₁-C₆haloalkyl, —C(═O)—O—(R⁵), —C(═O)—(R⁶), C₃-C₁₀cycloalkyl, and a 4-to 10-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, wherein the C₁-C₈alkyl and C₁-C₆haloalkyl areeach independently substituted with 0-3 occurrences of R^(3a), andwherein the C₃-C₁₀cycloalkyl and 4- to 10-membered heterocyclyl are eachindependently substituted with 0-3 occurrences of R^(3b);

or

R³ together with the nitrogen atom to which it is attached and R²together with the carbon atom to which it is attached form a 5- or6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N, O and S, which 5- or 6-membered heterocyclyl is substituted with0-2 occurrences of an oxo group;

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to10-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, C₆-C₁₀aryl, and —NR^(4b)R^(4c), wherein the C₁-C₆alkyl issubstituted with 0-1 occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R^(4b) is selected from hydrogen, and C₁-C₆alkyl;

R^(4c) is selected from hydrogen, C₁-C₆alkyl, and C₃-C₈cycloalkyl;

R⁵ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl;

R⁶ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, a 4- to10-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, and and —NR^(4b)R^(4c), wherein the C₁-C₆alkylis substituted with 0-1 occurrence of R^(6a), the C₃-C₈cycloalkyl issubstituted with 0-1 occurrence of R^(6b), and the 4- to 10-memberedheterocyclyl is substituted with 0-1 occurrence of C₁-C₆alkyl;

R^(6a) is selected from C₆-C₁₀aryl and C₃-C₈cycloalkyl;

R^(6b) is selected from halo, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, andC₁-C₆alkyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

p is 0 or 1.

Embodiment 2. A compound of Formula (I′) or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, wherein:

is a single bond or a double bond;

X is selected from CH, CF, and N;

R′ is selected from hydrogen and C₁-C₆alkyl;

R¹ is selected from hydrogen and C₁-C₆alkyl;

each R² is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo,and oxo, wherein the C₁-C₆alkyl is substituted with 0-1 occurrence ofR^(2a); or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form a bridgingring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;

R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴,C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and —C(═O)—(R⁶), wherein the C₁-C₈alkyland C₁-C₆haloalkyl are independently substituted with 0-3 occurrences ofR^(3a);

or

R³ together with the nitrogen atom to which it is attached and R²together with the carbon atom to which it is attached form a 5- or6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N, O and S;

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R⁵ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl;

R⁶ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, whereinthe C₁-C₆alkyl is substituted with 0-1 occurrence of R^(6a) and theC₃-C₈cycloalkyl is substituted with 0-1 occurrence of R^(6b);

R^(6a) is selected from C₆-C₁₀aryl and C₃-C₈cycloalkyl;

R^(6b) is selected from halo, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, andC₁-C₆alkyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

p is 0 or 1.

Embodiment 3. A compound of Formula (I) or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof,wherein:

X is selected from X is selected from CH, CF, and N;

R′ is selected from hydrogen and C₁-C₆alkyl;

R¹ is selected from hydrogen and C₁-C₆alkyl;

each R² is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo,and oxo, wherein the C₁-C₆alkyl is substituted with 0-1 occurrence ofR^(2a); or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form a bridgingring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;

R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴,C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and —C(═O)—(R⁶), wherein the C₁-C₈alkyland C₁-C₆haloalkyl are independently substituted with 0-3 occurrences ofR^(3a);

or

R³ together with the nitrogen atom to which it is attached and R²together with the carbon atom to which it is attached form a 5- or6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N, O and S;

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R⁵ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl;

R⁶ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, whereinthe C₁-C₆alkyl is substituted with 0-1 occurrence of R^(6a) and theC₃-C₈cycloalkyl is substituted with 0-1 occurrence of R^(6b);

R^(6a) is selected from C₆-C₁₀aryl and C₃-C₈cycloalkyl;

R^(6b) is selected from halo, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, andC₁-C₆alkyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

p is 0 or 1.

Embodiment 4. The compound of any one of Embodiments 1 to 3, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein

X is selected from CH, CF, and N;

R′ is selected from hydrogen and C₁-C₃alkyl;

R¹ is selected from hydrogen and C₁-C₃alkyl;

each R² is independently selected from unsubstituted C₁-C₆alkyl,C₁-C₆haloalkyl and halo; or 2 R² on non-adjacent carbon atoms togetherwith the non-adjacent carbon atoms to which they are attached form abridging ring;

R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴,C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and —C(═O)—(R⁶), wherein the C₁-C₈alkyland C₁-C₆haloalkyl are independently substituted with 0-3 occurrences ofR^(3a);

or

R³ together with the nitrogen atom to which it is attached and R²together with the carbon atom to which it is attached form a 5- or6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N and 0;

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R⁵ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl;

R⁶ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, whereinthe C₁-C₆alkyl is substituted with 0-1 occurrence of R^(6a) and theC₃-C₈cycloalkyl is substituted with 0-1 occurrence of R^(6b);

R^(6a) is selected from C₆-C₁₀aryl and C₃-C₈cycloalkyl;

R^(6b) is selected from chloro, fluoro, C₁-C₆haloalkyl,C₁-C₆haloalkoxyl, and C₁-C₆alkyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S;

n is 0, 1, 2 or 3;

m is 0, 1 or 2; and

p is 0 or 1.

Embodiment 5. The compound of any one of the preceding Embodiments, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein

X is selected from CH and N;

R′ is selected from hydrogen and methyl;

R¹ is selected from hydrogen and methyl;

each R² is independently selected from unsubstituted C₁-C₆alkyl andhalo; or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form aC₁-C₃alkylene bridging ring;

R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴,C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and —C(═O)—(R⁶), wherein the C₁-C₈alkyland C₁-C₆haloalkyl are independently substituted with 0-3 occurrences ofR^(3a);

or

R³ together with the nitrogen atom to which it is attached and R²together with the carbon atom to which it is attached form a 5- or6-membered heterocyclyl comprising 0-1 additional O heteroatom;

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S and phenyl, whereinthe C₃-C₁₀cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-memberedheteroaryl and phenyl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R⁵ is selected from C₁-C₆alkyl, C₃-C₆cycloalkyl, and C₆-C₁₀aryl;

R⁶ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, whereinthe C₁-C₆alkyl is substituted with 0-1 occurrence of R^(6a) and theC₃-C₈cycloalkyl is substituted with 0-1 occurrence of R^(6b);

R^(6a) is selected from C₆-C₁₀aryl and C₃-C₈cycloalkyl;

R^(6b) is selected from chloro, fluoro, C₁-C₆haloalkyl,C₁-C₆haloalkoxyl, and C₁-C₆alkyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S;

n is 0, 1, 2 or 3;

m is 0, 1 or 2; and

p is 0 or 1.

Embodiment 6. The compound of any one of the preceding Embodiments, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein

X is selected from CH and N;

R′ is hydrogen;

R¹ is hydrogen;

each R² is independently selected from unsubstituted C₁-C₆alkyl andfluoro; or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form aC₁-C₃alkylene bridging ring;

R³ is selected from C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴ and C₁-C₆haloalkyl,wherein the C₁-C₈alkyl is substituted with 0-2 occurrences of R^(3a) andthe C₁-C₆haloalkyl is substituted with 0-1 occurrence of R^(3a);

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N and O, a 5- to 6-membered heteroaryl comprising 1-3heteroatoms independently selected from N, O, and S and phenyl, whereinthe C₃-C₁₀cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-memberedheteroaryl and phenyl are substituted with 0-4 occurrences of R^(3b).

each R^(3b) is independently selected from halo, C₁-C₆haloalkyl,C₁-C₆haloalkoxyl, C₁-C₆alkyl, and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

n is 0, 1, 2 or 3;

m is 1 or 2; and

p is 0 or 1.

Embodiment 7. The compound of any one of the preceding Embodiments, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein

X is selected from CH and N;

R′ is hydrogen;

R¹ is hydrogen;

each R² is independently selected from unsubstituted C₁-C₆alkyl; or 2 R²on non-adjacent carbon atoms together with the non-adjacent carbon atomsto which they are attached form a C₁-C₃alkylene bridging ring;

R³ is selected from C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴ and unsubstitutedC₁-C₆haloalkyl, wherein the C₁-C₈alkyl is substituted with 0-2occurrences of R^(3a);

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N and O, a 5- to 6-membered heteroaryl comprising 1-3heteroatoms independently selected from N, O, and S and phenyl, whereinthe C₃-C₁₀cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 6-memberedheteroaryl and phenyl are substituted with 0-3 occurrences of R^(3b);

each R^(3b) is independently selected from halo, C₁-C₆haloalkyl,C₁-C₆haloalkoxyl, C₁-C₆alkyl, and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

n is 0, 1 or 2;

m is 1 or 2; and

p is 1.

Embodiment 8. The compound of any one of the preceding Embodiments, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein

X is selected from CH and N;

R′ is hydrogen;

R¹ is hydrogen;

each R² is independently selected from unsubstituted C₁-C₃alkyl;

R³ is selected from C₁-C₆alkyl, C₂-C₆alkenyl, —SO₂R⁴ and unsubstitutedC₁-C₆haloalkyl, wherein the C₁-C₆alkyl is substituted with 0-2occurrences of R^(3a);

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1 O heteroatom, a 6-memberedheteroaryl comprising 1-2 N heteroatoms and phenyl, wherein theC₃-C₁₀cycloalkyl, 4- to 6-membered heterocyclyl, 6-membered heteroaryland phenyl are substituted with 0-2 occurrences of R^(3b);

each R^(3b) is independently selected from chloro, fluoro,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl and C₁-C₆alkyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1 O heteroatom and phenyl, wherein theC₁-C₆alkyl is substituted with 1 occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl and phenyl;

n is 0, 1 or 2;

m is 1 or 2; and

p is 1.

Embodiment 9. The compound of Embodiment 1, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, of Formula (Ia″):

Embodiment 10. The compound of any one of Embodiments 1 and 2, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Ia′):

Embodiment 11. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Ia):

Embodiment 12. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein R³ is selected fromC₁-C₆alkyl and —CH₂—R^(3a) Embodiment 13. The compound of of any one ofEmbodiments 1 and 9, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, of Formula (Ib″):

Embodiment 14. The compound of of any one Embodiments 1, 2, 9 and 10, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Ib′):

Embodiment 15. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Ib):

Embodiment 16. The compound of any one of Embodiments 1 and 9, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Ic″), wherein:

is a single bond or a double bond;

X is selected from CH, CF and N;

R^(x) is selected from hydrogen, C₁-C₆alkyl, halo (e.g., F, Cl),C₁-C₆alkoxyl, and C₃-C₈cycloalkyl;

R^(2b) is selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and halo,wherein the C₁-C₆alkyl is substituted with 0-1 occurrence of R^(2a);

R^(2c) is selected from hydrogen and C₁-C₆alkyl, wherein the C₁-C₆alkylis substituted with 0-1 occurrence of R^(2a);

or R^(2b) and R^(2c) together with the carbon atoms to which they areattached form an oxo group;

each of R^(2d) and R^(2e) is independently selected from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and oxo, wherein the C₁-C₆alkyl issubstituted with 0-1 occurrence of R^(2a);

R^(2f) is hydrogen;

or R^(2b) and R^(2e) or R^(2b) and R^(2f) together with the carbon atomsto which they are attached form a bridging ring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl; and

R³ is defined according to any one of the preceding Embodiments.

Embodiment 17. The compound of any one of Embodiments 1, 2, 9 and 10, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Ic′), wherein:

is a single bond or a double bond;

X is selected from CH, CF and N;

R^(2b) is selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and halo,wherein the C₁-C₆alkyl is substituted with 0-1 occurrence of R^(2a);

R^(2c) is selected from hydrogen and C₁-C₆alkyl, wherein the C₁-C₆alkylis substituted with 0-1 occurrence of R^(2a);

or R^(2b) and R^(2c) together with the carbon atoms to which they areattached form an oxo group;

each of R^(2d) and R^(2e) is independently selected from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and oxo, wherein the C₁-C₆alkyl issubstituted with 0-1 occurrence of R^(2a);

R^(2f) is hydrogen;

or R^(2b) and R^(2e) or R^(2b) and R^(2f) together with the carbon atomsto which they are attached form a bridging ring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl; and

R³ is defined according to any one of the preceding Embodiments.

Embodiment 18. The compound of any one of Embodiments 1 to 12, 16 and17, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Ic), wherein:

X is selected from CH, CF and N;

R^(2b) is selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, and halo,wherein the C₁-C₆alkyl is substituted with 0-1 occurrence of R^(2a);

R^(2c) is selected from hydrogen and C₁-C₆alkyl, wherein the C₁-C₆alkylis substituted with 0-1 occurrence of R^(2a);

or R^(2b) and R^(2c) together with the carbon atoms to which they areattached form an oxo group;

each of R^(2d) and R^(2e) is independently selected from hydrogen,C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and oxo, wherein the C₁-C₆alkyl issubstituted with 0-1 occurrence of R^(2a);

R^(2f) is hydrogen;

or R^(2b) and R^(2e) or R^(2b) and R^(2f) together with the carbon atomsto which they are attached form a bridging ring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl; and

R³ is defined according to any one of the preceding Embodiments.

Embodiment 19. The compound of any one of Embodiments 16 to 18, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein

X is selected from CH and N;

R^(2b) is selected from hydrogen, C₁-C₃alkyl, C₁-C₃haloalkyl, and halo,wherein the C₁-C₃alkyl is substituted with 0-1 occurrence of R^(2a);

R^(2c) is selected from hydrogen and C₁-C₃alkyl, wherein the C₁-C₃alkylis substituted with 0-1 occurrence of R^(2a);

or R^(2b) and R^(2c) together with the carbon atoms to which they areattached form an oxo group;

each of R^(2d) and R^(2e) is independently selected from hydrogen,C₁-C₃alkyl, C₁-C₃haloalkyl, halo, and oxo, wherein the C₁-C₃alkyl issubstituted with 0-1 occurrence of R^(2a);

R^(2f) is hydrogen;

or R^(2b) and R^(2e) or R^(2b) and R^(2f) together with the carbon atomsto which they are attached form a bridging ring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;

R³ is selected from C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴, C₁-C₆haloalkyl,—C(═O)—O—(R⁵) and —C(═O)—(R⁶), wherein the C₁-C₈alkyl and C₁-C₆haloalkylare independently substituted with 0-3 occurrences of R^(3a);

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R⁵ is selected from C₁-C₆alkyl and C₆-C₁₀aryl;

R⁶ is selected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, whereinthe C₁-C₆alkyl is substituted with 0-1 occurrence of R^(6a) and theC₃-C₈cycloalkyl is substituted with 0-1 occurrence of R^(6b);

R^(6a) is selected from C₆-C₁₀aryl and C₃-C₈cycloalkyl;

R^(6b) is selected from halo, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, andC₁-C₆alkyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S; and

m is 1 or 2.

Embodiment 20. The compound of any one of Embodiments 16 to 19, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein

X is selected from CH and N;

each of R^(2b), R^(2c), R^(2d) and R^(2e) is independently selected fromhydrogen and unsubstituted C₁-C₃alkyl;

R^(2f) is hydrogen;

or R^(2b) and R^(2e) or R^(2b) and R^(2f) together with the carbon atomsto which they are attached form a C₁-C₃alkylene bridging ring;

R³ is selected from C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴, andC₁-C₆haloalkyl, wherein the C₁-C₈alkyl and C₁-C₆haloalkyl areindependently substituted with 0-3 occurrences of R^(3a);

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;

R⁷ is selected from hydrogen and C₁-C₆alkyl;

R⁸ is selected from hydrogen and C₁-C₆alkyl;

or

R⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S; and

m is 1 or 2.

Embodiment 21. The compound according to any of Embodiments 16 to 20, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein

X is selected from CH and N;

each of R^(2b), R^(2c), R^(2d) and R^(2e) is independently selected fromhydrogen and unsubstituted C₁-C₃alkyl;

R^(2f) is hydrogen;

R³ is selected from C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴, andC₁-C₆haloalkyl, wherein the C₁-C₈alkyl and C₁-C₆haloalkyl areindependently substituted with 0-3 occurrences of R^(3a);

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S and phenyl, whereinthe C₃-C₁₀cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-memberedheteroaryl and phenyl are substituted with 0-4 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, and hydroxyl;

R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 1occurrence of R^(4a);

R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;and

m is 1.

Embodiment 22. The compound of any one of Embodiments 1, 9 and 16, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Id″), wherein:

R^(2b), R^(2c) and R^(2e) are defined according to any of Embodiments 16to 21.

Embodiment 23. The compound of any one of Embodiments 1, 2, 9, 10, 16,17 and 22, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, of Formula (Id′), wherein:

R^(2b), R^(2c) and R^(2e) are defined according to any of Embodiments 16to 21.

Embodiment 24. The compound of any one of Embodiments 1 to 12 and 16 to23, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Id), wherein:

R^(2b), R^(2c) and R^(2e) are defined according to any of Embodiments 16to 21.

Embodiment 25. The compound of any one of Embodiments 1 to 12 and 16 to24, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Id-1), wherein:

R^(2b) is selected from hydrogen and C₁-C₄alkyl; and

X and R³ are defined according to any one of the preceding Embodiments.

Embodiment 26. The compound Embodiment 25, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, wherein:

X is CH or N;

R^(2b) is selected from hydrogen and C₁-C₄alkyl;

R³ is selected from C₁-C₈alkyl, —SO₂R⁴, and —C(═O)—(R⁶), wherein theC₁-C₈alkyl is independently substituted with 0-3 occurrences of R^(3a);

each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, C₁-C₆alkoxyl, and hydroxyl, wherein theC₃-C₁₀cycloalkyl and 4- to 6-membered heterocyclyl are substituted with0-2 occurrences of R^(3b);

each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂R⁴, and hydroxyl.

Embodiment 27. The compound of any one of Embodiments 25 and 26, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Id-2) or (Id-3):

Embodiment 28. The compound of any one of Embodiments 1, 9, 13, 16 and22, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Ie″), wherein:

R^(2b), R^(2c) and R^(2e) are defined according to any of Embodiments 16to 21.

Embodiment 29. The compound of any one Embodiments 1, 2, 9, 10, 13, 14,16, 17, 22, 23 and 28, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, of Formula (Ie′),wherein:

R^(2b), R^(2c) and R^(2e) are defined according to any of Embodiments 16to 21.

Embodiment 30. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, of Formula (Ie), wherein:

R^(2b), R^(2c) and R^(2e) are defined according to any of Embodiments 16to 21.

Embodiment 31. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein X is CH.

Embodiment 32. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein X is N.

Embodiment 33. The compound of any one of Embodiments 1 to 15, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein n is selected from 0 and 1,and m is selected from 1 and 2.

Embodiment 34. The compound of any one of Embodiments 1 to 15, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein R² is unsubstitutedC₁-C₆alkyl, e.g., methyl, and n is 1.

Embodiment 35. The compound of any one of Embodiments 1 to 20 and 33, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein m is 1.

Embodiment 36. The compound of any one of Embodiments 1 to 12, 16 to 27,and 31 to 35, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, wherein R³ is C₁-C₆alkyl,wherein the C₁-C₆alkyl is substituted with 1 occurrence of R^(3a).

Embodiment 37. The compound of any one of Embodiments 1 to 12, 16 to 27,and 31 to 36, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, wherein R³ is selected frommethyl, ethyl, n-propyl, i-propyl, 2-propanyl, butyl, i-butyl,2-butanyl, 3-methyl-2-butanyl, i-pentyl, 3-pentanyl, neopentyl,2,4-dimethylpentanyl, and —CH₂—(CH₂)₀₋₁—R^(3a).

Embodiment 38. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein R^(3a) is C₃-C₁₀cycloalkyl,wherein the C₃-C₁₀cycloalkyl is substituted with 0-4 occurrences ofR^(3b), wherein each R^(3b) is independently selected from C₁-C₆alkoxyl,chloro, fluoro, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl and C₁-C₆alkyl.

Embodiment 39. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein R^(3a) is selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantanyl,

Embodiment 40. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein R^(3a) is C₃-C₇cycloalkyl,wherein the C₃-C₇cycloalkyl is substituted with 0-2 occurrences offluoro.

Embodiment 41. The compound of any one of Embodiments 16 to 40, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein each of R^(2b) and R^(2e) isindependently selected from hydrogen and unsubstituted C₁-C₃alkyl; andR^(2c) is hydrogen.

Embodiment 42. The compound of any one of Embodiments 16 to 41, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein each of R^(2b) and R^(2e) isindependently selected from hydrogen and methyl; and R^(2c) is hydrogen.

Embodiment 43. The compound of any one of Embodiments 16 to 42, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein R^(2b) is unsubstitutedC₁-C₃alkyl (e.g., methyl); R^(2c) is hydrogen; and R^(2e) is selectedfrom hydrogen and unsubstituted C₁-C₃alkyl.

Embodiment 44. The compound of any one of Embodiments 16 to 43, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein R^(2b) is methyl and R^(2c),R^(2d), R^(2e) and R^(2f) are all hydrogen.

Embodiment 45. The compound of any one of Embodiments 1 to 15 and 31 to44, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, wherein R² is unsubstitutedC₁-C₃alkyl, and n is 1.

Embodiment 46. The compound of any one of Embodiments 1, 2, 4 to 10, 12to 14, 16, 17, 19 to 23, 28, 29 and 31 to 45, wherein

is a double bond.

Embodiment 47. The compound of any one of the preceding Embodiments

is a single bond.

Embodiment 48. The compound of Embodiment 1 or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, selected from:

1-(5-((1-(((1s,4s)-4- methoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(5-fluoro-2-methylbenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4-(1H,3H)dione

1-(5-((1-(((1r,4r)-4- methoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo}[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

methyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-one

1-(5-((1-acetylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(4-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclopentylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

phenyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((1R,5S)-8-isobutyl-8- azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-one

1-(5-((1-(cyclopentylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(thiazol-2-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((4,4- difluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S,5S)-4-isobutyl-3,5-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(cyclopropylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-ethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-one

1-(5-((1-(2-oxo-2-(piperidin-1-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(2-cyclohexylethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isobutyrylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-fluoro-1-isobutylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1- ((cyclopropylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2-methylbenzyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclopentylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((1R,5S)-8-(pyridin-3-ylmethyl)-8- azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((tetrahydro-2H-pyran-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-(4-fluorobenzyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(pyridin-2-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-((4,4-difluorocyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(2-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(cyclobutylmethyl)-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,4S)-4- methoxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((3-ethyl-4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-(2-fluoro-2-methylpropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1s,4R)-4- methoxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-(3-methylbenzyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cycloheptylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(thiazol-4-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4S)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-(cyclohexylmethyl)-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((3-methyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-(cyclohexylmethyl)-3- (methoxymethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methylbutyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(3-fluorobenzyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclohexylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(R)-1-(5-((4-isobutyl-3- (methoxymethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexanecarbonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((2-methyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclopentylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-(pyridin-3-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(heptan-4-yl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-hydroxy-2- (hydroxymethyl)propyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclobutylethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((1-methyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((3,3-dimethyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isopentyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(isopropylsulfonyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclopentylethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-((3,3-difluorocyclobutyl)methyl)-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(R)-1-(5-((1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-(cyclobutylmethyl)-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-((4,4- difluorocyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((1-(isopropylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(3,3,3-trifluoro-2,2- dimethylpropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-((3,3-difluorocyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

isobutyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((4-(cycloheptylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-(cyclohexylmethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(((1r,4r)-4- methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,4R)-5-(cyclohexylmethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(pyridin-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((1- (trifluoromethyl)cyclopropyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isobutylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2,2,3,3-tetrafluoropropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclobutylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-((3,3- difluorocyclobutyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

cyclohexyl 4-((3-(2,4- dioxotetrahydropyrimdiin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((1-(oxetan-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((1-methyl-1H-imidazol-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-((tetrahydrofuran-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-isobutyl-3,3-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(3-phenylpropanoyl)piperidin-4-yl)mehtyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclobutylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(thiazol-4-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isopentylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(1-(pyridin-3-yl)ethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)dione

(S)-1-(5-((4-(cyclobutylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-((1-methyl-1H-imidazol-4-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-(((1s,4s)-4- methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((3,3- difluorocyclobutyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((1r,4r)-4- ethoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,4R)-5-(pyridin-3-ylmethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclopentylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(sec-butylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-benzoylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S)-2-methyl-4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-(2-cyclohexylethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-((tetrahydro-2H-pyran-3-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(3-cyclohexylpropanoyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-isobutylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-(pyridin-3-ylmethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(pentan-3-yl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-neopentylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1S,4S)-5-(isopropylsulfonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(isobutylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-(3-fluorobenzyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((3-(difluoromethyl)-4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((3-methyl-4-(2-(tetrahydro-2H- pyran-4-yl)ethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2-cyclohexylethyl)-3-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclohexylmethyl)-3-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(1-(pyridin-3-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1S,4S)-5-(pyridin-3-ylmethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(benzylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1S,4S)-5-(cyclohexylmethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclobutylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-isopropylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methyl-1-(tetrahydro-2H-pyran-4- yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-(cyclohexylmethyl)-3- (difluoromethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,4R)-5-(isopropylsulfonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-isobutyl-2-oxopiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-isopropyl-4-((tetrahydro-2H- pyran-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(methylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclohexylmethyl)-2-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-ethylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((3-methyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((tetrahydrofuran-3-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(((3r,5r,7r)-adamantan-1-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cycloheptylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(1-phenylethyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclobutylpropan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-(trifluoromethoxy)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-4-(((2R,6S)-2,6- dimethyltetrahydro-2H-pyran-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-propylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cycloheptylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-phenethylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo∥,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((2-methyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-3-methyl-4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(pyridin-4-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S,5R)-4-isobutyl-3,5-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(1-(1-isobutylpiperidin-4- yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-benzylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-benzyl-4-fluoropiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,2,3,3-tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((3,3- difluorocyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(phenylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(((3r,5r,7r)-adamantan-1-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-((5-fluoropyridin-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2R,4R)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methoxyethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3,3,3-trifluoro-2,2- dimethylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,4-dimethylpentan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4S)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((5-methylpyridin-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4S)-1-isobutyl-2-methylpiepridin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-(cyclohexylmethyl)-8- azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-3-methyl-4-((tetrahydrofuran-2-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-isopropylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclohexylmethyl)-3,3-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4S)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4S)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((tetrahydrofuran-2-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(R)-1-(5-((hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4R)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(R)-1-(5-((4-(cyclohexylmethyl)-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(3-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methylbenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,4S)-4- hydroxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(3-fluoro-2-methylbenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4S)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3,5-difluorobenzyl)piepridin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4S)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3,4-difluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-methylbutan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(pentan-3-yl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(3-methylbutan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((6-methylpyridin-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-((4,4-dimethylcyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(4-methylbenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperidin-4- yl)methyl)pyrazolo∥,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S,5S)-4-(cyclohexylmethyl)-3,5-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo∥,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pryidn-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- dimethylcyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-benzylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(pyridin-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo∥,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(cyclohexylmethyl)-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((1r,4r)-4- hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,4S)-4- methoxycyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(2-methylallyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridni-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1,4-diazepan-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-isobutyl-1,4-diazepan-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclohexylmethyl)-1,4-diazepan-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(1-(3-fluorophenyl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-((1-methyl-1H-pyrazol-5-yl)methyl)piperidin-4-yl)methyl)pyrazolo∥,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-isobutylazetidin-3- yl)methyl)pyrazolo∥,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(cyclohexylmethyl)azetidin-3-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-methylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexylmethyl)pyrrolidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,4-difluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-isobutyl-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclobutylmethyl)pyrrolidin-3-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-fluoro-5- (trifluoromethyl)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-fluorobenzyl)pyrrolidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-(1H-imidazol-4-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isobutylpyrrolidin-3- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclohexyl-2,2- difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((3R,4S)-3,4-difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo∥,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-isopropylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimdiine-2,4(1H,3H)-dione

(R)-1-(5-((octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)pyrazolo∥,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isobutyl-2,2-dimethylpiperidn-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(((1r,4r)-4- hydroxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridn-3- yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,3-difluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(isopropylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(R)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

1-(5-(((1S,4R)-2-methyl-1-(2,2,3,3- tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((6-(trifluoromethyl)pyridin-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-1-(((1s,3R)-3-methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((S)-4-(((1s,3R)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-((1- (trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((1s,3s)-3- methoxycyclobutyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,3S)-3-methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,3S)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-(4-(trifluoromethoxy)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((3R,4S)-3,4- difluorocyclopentyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-4-(((3R,4S)-3,4- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((9aR)-octahydro-2H-quinolizin-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(isopropylsulfonyl)-2-mehtylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(2,2,3,3- tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,3S)-3-methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1s,3R)-3-methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,3S)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo∥,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((S)-4-(((1s,3R)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-1-(((R)-3,3-difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((S)-3,3-difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo∥,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((R)-3,3- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((S)-4-(((S)-3,3- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-1-(((1r,3R,4S)-3,4-difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,3R,4S)-3,4- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(azepan-4-ylmethyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

tert-butyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pryidin-5- yl)methyl)azepane-1-carboxylate

1-(5-(((1-methylazepan-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexylmethyl)azepan-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(2,2,3,3- tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(2,2-difluoroethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-2-methyl-1-(2,2,2- trifluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3- yl)dihydropyrimidine-2,4(1H,3H)-dine

1-(5-(((2S,4R)-2-methyl-1-(3,3,3- trifluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(oxetan-2-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-1-(2,2-difluoro-3- methoxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo∥,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-1-cyclobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(oxetan-3-yl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-cyclobutylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-2-methyl-1- (methylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(isopropylsulfonyl)-2-mehtylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4)R-1-(cyclopropylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-1-isobutyryl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclobutanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-2-methyl-1-(1- methylpiperidine-4-carbonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(pyrrolidin-1-ylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(2S,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N,N,2-trimethylpiperidine-1-sulfonamide

(2S,4R)-N-cyclopentyl-4-((3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2- methylpiperidine-1-sulfonamide

(2S,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N,N,2-trimethylpiperidine-1-carboxamide

1-(5-(((2S,4R)-2-methyl-1-(pyrrolidine-1-carbonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(2S,4R)-N-cyclopentyl-4-((3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2- methylpiperidine-1-carboxamide

1-(5-((1-(pyrrolidin-1-ylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

N-cyclopentyl-4-((3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo∥,5-a]pyridin-5- yl)methyl)piperidine-1-sulfonamide

(2S,4R)-4-((3-(2,4-dioxotetrahydropyrimdiin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N-ethyl-N,2-dimethylpiperidine-1- carboxamide

1-(5-((1-(((1s,3s)-3- methoxycyclobutyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioen

1-(5-((1-(((1r,3R,4S)-3,4- difluorocyclopentyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,3S)-3-methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4)R-1-(((1s,3R)-3-methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,3R,4S)-3,4-difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((R)-3,3-difluroocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((S)-3,3-difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4S)-1-((4,4- difluorocyclohexyl)methyl)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4S)-4-fluoro-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((2S,4R)-4-fluoro-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-((1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((octahydro-2H-pyrido[1,2-a]pryazin-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)pyrazolo[,15-a]pryidin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((1,1-dioxidohexahydro-5H- isothiazolo[2,3-a]pyrazin-5-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-5-(((S)-4-(((1r,3S)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((S)-4-(((1s,3R)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyimidine-2,4(1H,3H)- dione

1-(5-(((S)-4-(((1r,3R,4S)-3,4- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((S)-4-(((R)-3,3- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(((S)-4-(((S)-3,3- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((3-methyl-4-((1- methylcyclobutyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-3-methyl-4-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-3-methyl-4-(oxetan-2-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1,3H)- dione

(S)-1-(5-((4-((2-oxaspiro[3.3]heptan-6- yl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-((6,6-difluorospiro[3.3]heptan-2-yl)methyl)-3-methylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-(((4-(2,2-difluoroethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-(2,2-difluoro-3-methoxypropyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-cyclobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((3-methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(2-oxaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-cyclohexyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(4,4-difluorocyclohexyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((3-methyl-4-(spiro[3.3]heptan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((3-methyl-4-(2-methyl-2- azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridn-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-cyclohexylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(ethylsulfonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-isobutyryl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclohexanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

(S)-1-(5-((4-(cyclobutanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

1-(5-(1-(4-isobutylpiperazin-1- yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclopropylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine- 2,4-(1H,3H)-dione

5-fluoro-1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

5-chloro-1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)pyrimidin-2,4(1H,3H)-dione

1-(5-(((2S,4)R-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methoxypyrimidine-2,4(1H,3H)-dione

5-cyclopropyl-1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pryidin-3-yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-fluoro-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methoxypyrimidine-2,4(1H,3H)-dione

(S)-5-cyclopropyl-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-((4,4-difluorocyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Embodiment 49. The compound of any one of the preceding Embodiments, ora pharmaceutically acceptable salt, thereof, wherein thepharmaceutically acceptable salt is an acid addition salt.

Embodiment 50. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of any of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, and a pharmaceutically acceptablecarrier or excipient.

Embodiment 51. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use as a medicament.

Embodiment 52. A method of treating or preventing a disease or disorderin a subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of any one ofEmbodiments 1 to 49, or a pharmaceutically acceptable salt, thereof.

Embodiment 53. A method of treating or preventing a disorder that isaffected by the reduction of WIZ protein levels, in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a compound of any one of Embodiments1 to 49, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof.

Embodiment 54. A method of treating a disease or disorder that isaffected by the modulation of WIZ protein levels comprisingadministering to the patient in need thereof a compound of any one ofEmbodiments 1 to 49, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 55. A method of inhibiting WIZ protein expression in asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of any one ofEmbodiments 1 to 49, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 56. A method of degrading WIZ protein in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a compound of any one of Embodiments1 to 49, or a pharmaceutically acceptable salt, thereof.

Embodiment 57. A method of inhibiting, reducing, or eliminating theactivity of WIZ protein or WIZ protein expression, the method comprisingadministering to the subject a compound of any one of Embodiments 1 to49, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Embodiment 58. A method of inducing or promoting fetal hemoglobin in asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of any one ofEmbodiments 1 to 49, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 59. A method of reactivating fetal hemoglobin production orexpression in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of any one of Embodiments 1 to 49, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Embodiment 60. A method of increasing fetal hemoglobin expression in asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of any one ofEmbodiments 1 to 49, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

Embodiment 61. A method of treating a hemoglobinopathy, e.g., abeta-hemoglobinopathy, in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Embodiment 62. A method of treating a sickle cell disease in a subjectin need thereof, the method comprising administering to the subject atherapeutically effective amount of a compound of any one of Embodiments1 to 49, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof.

Embodiment 63. A method of treating beta-thalassemia in a subject inneed thereof, the method comprising administering to the subject atherapeutically effective amount of a compound of any one of Embodiments1 to 49, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof.

Embodiment 64. A method for reducing WIZ protein levels in a subjectcomprising the step of administering to a subject in need thereof atherapeutically effective amount of a compound of any one of Embodiments1 to 49, or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof.

Embodiment 65. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in treating or preventing adisease or disorder in a subject in need thereof.

Embodiment 66. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder selected from sickle cell disease and beta-thalassemia.

Embodiment 67. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in treating or preventing adisorder that is affected by the inhibition of WIZ protein levels, in asubject in need thereof.

Embodiment 68. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in treating or preventing adisorder that is affected by the reduction of WIZ protein levels, in asubject in need thereof.

Embodiment 69. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment orprevention of a disease or disorder that is affected by the degradationof WIZ protein.

Embodiment 70. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in inhibiting, reducing, oreliminating the activity of WIZ protein or WIZ protein expression in asubject in need thereof.

Embodiment 71. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in inducing or promotingfetal hemoglobin in a subject in need thereof.

Embodiment 72. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in reactivating fetalhemoglobin production or expression in a subject in need thereof.

Embodiment 73. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in increasing fetalhemoglobin expression in a subject in need thereof.

Embodiment 74. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in treating ahemoglobinopathy in a subject in need thereof.

Embodiment 75. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in treating a sickle celldisease in a subject in need thereof.

Embodiment 76. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in treating beta-thalassemiain a subject in need thereof.

Embodiment 77. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder affected by an increase in fetal hemoglobin expression.

Embodiment 78. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder affected by the inhibition, reduction, or elimination of theactivity of WIZ protein or WIZ protein expression.

Embodiment 79. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder affected by the induction or promotion of fetal hemoglobin.

Embodiment 80. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of a diseaseor disorder affected by the reactivation of fetal hemoglobin productionor expression.

Embodiment 81. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in inhibiting WIZ proteinexpression in a subject in need thereof.

Embodiment 82. A compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in degrading WIZ protein in asubject in need thereof.

Embodiment 83. Use of a compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, in the manufacture of a medicamentfor treating a disease or disorder that is affected by the reduction ofWIZ protein levels, inhibition of WIZ protein expression or degradationof WIZ protein.

Embodiment 84. Use of a compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, in the manufacture of a medicamentfor treating a disease or disorder that is affected by inducing orpromoting fetal hemoglobin.

Embodiment 85. Use of a compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, in the manufacture of a medicamentfor treating a disease or disorder that is affected by reactivatingfetal hemoglobin production or expression.

Embodiment 86. Use of a compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, in the manufacture of a medicamentfor treating a disease or disorder that is affected by increasing fetalhemoglobin expression.

Embodiment 87. The use of a compound of any one of Embodiments 83 to 86,wherein the disease or disorder is selected from sickle cell disease andbeta-thalassemia.

Embodiment 88. Use of a compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, in the treatment of a disease ordisorder that is affected by the reduction of WIZ protein levels,inhibition of WIZ protein expression or degradation of WIZ protein.

Embodiment 89. Use of a compound of any one of Embodiments 1 to 49, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, in the treatment of a disease ordisorder that is affected by inducing fetal hemoglobin, reactivatingfetal hemoglobin production or expression, or increasing fetalhemoglobin expression.

Embodiment 90. The use of Embodiment 88 or 89, wherein the disease ordisorder is selected from sickle cell disease and beta-thalassemia.

Embodiment 91. A pharmaceutical combination comprising a compound of anyone of Embodiments 1 to 49, or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and one ormore additional therapeutic agent(s).

Depending on the choice of the starting materials and procedures, thecompounds can be present in the form of one of the possible isomers oras mixtures thereof, for example as pure optical isomers, or as isomermixtures, such as racemates and diastereomeric mixtures, depending onthe number of asymmetric centres. The disclosure is meant to include allsuch possible isomers, including racemic mixtures, enantiomericallyenriched mixtures, diastereomeric mixtures and optically pure forms.Optically active (R)- and (S)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.If the compound contains a disubstituted or trisubstituted cycloalkyl,the cycloalkyl substituent(s) may have a cis- or trans-configuration.The disclosure includes cis and trans configurations of substitutedcycloalkyl groups as well as mixtures thereof. All tautomeric forms arealso intended to be included. In particular, where a heteroaryl ringcontaining N as a ring atom is 2-pyridone, for example, tautomers wherethe carbonyl is depicted as a hydroxy (e.g., 2-hydroxypyridine) areincluded.

Pharmaceutically Acceptable Salts

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the disclosure. “Salts” includein particular “pharmaceutically acceptable salts”. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compounds of thisdisclosure and, which typically are not biologically or otherwiseundesirable. The compounds of the disclosure may be capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids. Inorganic acids from which salts canbe derived include, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acidsfrom which salts can be derived include, for example, acetic acid,propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid,succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, formic acid, trifluoroaceticacid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases. Inorganic bases from which salts can bederived include, for example, ammonium salts and metals from columns Ito XII of the periodic table. In certain embodiments, the salts arederived from sodium, potassium, ammonium, calcium, magnesium, iron,silver, zinc, and copper; particularly suitable salts include ammonium,potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

In another aspect, the disclosure provides compounds in acetate,ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide,bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate,chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate,formate, fumarate, gluceptate, gluconate, glucuronate, glutamate,glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, mucate, naphthoate, napsylate,nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate,tartrate, tosylate trifenatate, trifluoroacetate or xinafoate salt form.

In another aspect, the disclosure provides compounds in sodium,potassium, ammonium, calcium, magnesium, iron, silver, zinc, copper,isopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine or tromethamine salt form.

Preferably, pharmaceutically acceptable salts of compounds of formulae(I), (Ia), (Ib), (Ic), (Id), and (Ie), are acid addition salts.

Isotopically Labelled Compounds

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, chlorine andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁸O, ¹⁵N, ¹⁸F, ¹⁷O, ¹⁸O, ³⁵S,³⁶Cl, ¹²³I, ¹²⁴I, ¹²⁵I respectively. The disclosure includes variousisotopically labeled compounds as defined herein, for example those intowhich radioactive isotopes, such as ³H and ¹⁴C, or those into whichnon-radioactive isotopes, such as ²H and ¹³C are present. Suchisotopically labelled compounds are useful in metabolic studies (with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques, such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT) including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F compound may be particularly desirablefor PET or SPECT studies. Isotopically-labeled compounds of formulae(I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′),(Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), and(Ie), can generally be prepared by conventional techniques known tothose skilled in the art or by processes analogous to those described inthe accompanying Examples and General Schemes (e.g., General Schemes 1to 5) using an appropriate isotopically-labeled reagent in place of thenon-labeled reagent previously employed.

In one embodiment of any aspect of the present disclosure, the hydrogensin the compound of Formula (I), Formula (I′) or Formula (I″) (andsubformulae thereof) are present in their normal isotopic abundances. Ina another embodiment, the hydrogens are isotopically enriched indeuterium (D), and in a particular embodiment of the disclosure thehydrogen(s) of the dihydrouracil (DHU) or the uracil portion incompounds of Formula (I) or Formula (I′) are enriched in D, for example,

Deuterated dihydrouracil and uracil moities can be prepared as describedin Hill, R. K. et al., Journal of Labelled Compounds andRadiopharmaceuticals, Vol. XXII, No. 2, p. 143-148.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formulae (I″), (I′), (I), (Ia″), (Ia′),(Ia), (Ib″), (Ib′), (b), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1),(Id-2), (Id-3), (Ie″), (Ie′), and (Ie). The concentration of such aheavier isotope, specifically deuterium, may be defined by the isotopicenrichment factor. The term “isotopic enrichment factor” as used hereinmeans the ratio between the isotopic abundance and the natural abundanceof a specified isotope. If a substituent in a compound of thisdisclosure is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates in accordance with the disclosureinclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g., D₂O, d₆-acetone, d₆-DMSO.

Compounds of the disclosure, i.e. compounds of formulae (I″), (I′), (I),(Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″),(Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), and (Ie), thatcontain groups capable of acting as donors and/or acceptors for hydrogenbonds may be capable of forming co-crystals with suitable co-crystalformers. These co-crystals may be prepared from compounds of (I″), (I′),(I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″),(Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), and (Ie) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formulae (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib),(Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″),(Ie′), and (Ie) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate thedisclosure and does not pose a limitation on the scope of the disclosureotherwise claimed.

Any asymmetric center (e.g., carbon or the like) of the compound(s) ofthe disclosure can be present in racemic or enantiomerically enriched,for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, for example, as a mixture of enantiomers, each asymmetriccenter is present in at least 10% enantiomeric excess, at least 20%enantiomeric excess, at least 30% enantiomeric excess, at least 40%enantiomeric excess, at least 50% enantiomeric excess, at least 60%enantiomeric excess, at least 70% enantiomeric excess, at least 80%enantiomeric excess, at least 90% enantiomeric excess, at least 95%enantiomeric excess, or at least 99% enantiomeric excess. In certainembodiments, for example, in enantiomerically enriched form, eachasymmetric center is present in at least 50% enantiomeric excess, atleast 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess.Thus, compounds of the disclosure can be present in a racemic mixture orin enantiomerically enriched form or in an enantiopure form or as amixture of diastereoisomers.

In the formulae of the present application the term “

” on a C-sp³ indicates the absolute stereochemistry, either (R) or (S).In the formulae of the present application the term “

” on a C-sp³ indicates the absolute stereochemistry, either (R) or (S).In the formulae of the present application the term “

” on a C-sp³ represents a covalent bond wherein the stereochemistry ofthe bond is not defined. This means that the term “

” on a C-sp³ comprises an (S) configuration or an (R) configuration ofthe respective chiral centre. Furthermore, mixtures may also be present.Therefore, mixtures of stereoisomers, e.g., mixtures of enantiomers,such as racemates, and/or mixtures of diastereoisomers are encompassedby the present disclosure.

For the avoidance of doubt, where compound structures are drawn withundefined stereochemistry with respect to any R group, for example, toR² in formula (I), as represented by a bond (

), this means the asymmetric center has either a (R)- or(S)-configuration, or exists as a mixture thereof and stated as such.

Accordingly, as used herein a compound of the disclosure can be in theform of one of the possible stereoisomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) stereoisomers, diastereomers, optical isomers,racemates or mixtures thereof.

Any resulting mixtures of stereoisomers can be separated on the basis ofthe physicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of compounds of the disclosure or ofintermediates can be resolved into the optical isomers (enantiomers) byknown methods, e.g., by separation of the diastereomeric salts thereof,obtained with an optically active acid or base, and liberating theoptically active acidic or basic compound. In particular, a basic moietymay thus be employed to resolve the compounds of the disclosure intotheir optical antipodes, e.g., by fractional crystallization of a saltformed with an optically active acid, e.g., tartaric acid, dibenzoyltartaric acid, diacetyl tartaric acid, di-O, O′-p-toluoyl tartaric acid,mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic compoundsof the disclosure or racemic intermediates can also be resolved bychiral chromatography, e.g., high pressure liquid chromatography (HPLC)using a chiral adsorbent.

Furthermore, the compounds of the disclosure, including their salts, canalso be obtained in the form of their hydrates, or include othersolvents used for their crystallization. The compounds of the disclosuremay inherently or by design form solvates with pharmaceuticallyacceptable solvents (including water); therefore, it is intended thatthe disclosure embrace both solvated and unsolvated forms. The term“solvate” refers to a molecular complex of a compound of the disclosure(including pharmaceutically acceptable salts thereof) with one or moresolvent molecules. Such solvent molecules are those commonly used in thepharmaceutical art, which are known to be innocuous to the recipient,e.g., water, ethanol, and the like. The term “hydrate” refers to thecomplex where the solvent molecule is water. The presence of solvatescan be identified by a person of skill in the art with tools such asNMR.

The compounds of the disclosure, including salts, hydrates and solvatesthereof, may inherently or by design form polymorphs.

Methods of Making

The compounds of the disclosure can be prepared in a number of ways wellknown to those skilled in the art of organic synthesis. By way ofexample, compounds of the present disclosure can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art.

Generally, the compounds of formula (I″), formula (I) and formula (I′)can be prepared according to the Schemes provided infra.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe disclosure are prepared in the above reaction Scheme 1 as follows:

A cross-coupling reaction, such as a palladium (Pd)-catalysed couplingof I-1 with a boraneyl coupling partner of formula I-2A (prepared byhydroboration of an appropriate alkene with 9-BBN, for example) in thepresence of a polar solvent, such as N,N-dimethylformamide (DMF), asuitable ligand such as dppf, and a base such as potassium carbonate(K₂CO₃) can provide the cross-coupled product 1-3 in Step 1, where X isCH. Removal of the protecting group (e.g., Boc) under acidic conditionsat room temperature can provide the free amine I-4A, whereZ=2,4-dimethoxybenzyl (DMB). Alternatively, removal of the protectinggroups under acidic conditions and heating can provide I-4B (Step 2).I-4A and I-4B can then be converted respectively to I-5A and I-5B via areductive amination (Step 3-i) with an appropriate aldehyde in thepresence of a borohydride reagent, such as sodium borohydride acetate.Alternatively, by an alkylation reaction (Step 3-ii) with an appropriatealkyl halide, mesylate, tosylate or triflate in the presence of an amineor carbonate base and polar solvent, such as diisopropylethylamine(DIPEA) or potassium carbonate (K₂CO₃) and dimethylformamide (DMF).Alternatively, by an amide coupling reaction (Step 3-iii) of thecompound with an appropriate carboxylic acid, an activating agent, suchas HATU, and a base such as DIPEA, when R³ forms an amide with thenitrogen to which it is attached. Alternatively, by an acylation orsulfonylation reaction (Step 3-iv) with an appropriate acyl chloride orsulfonyl chloride and a base such as DIPEA or TEA, where R³ forms anamide or sulfonamide with the nitrogen to which it is attached. Removalof the protecting group of I-5A under acidic conditions and heating canprovide I-5B (Step 4).

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe disclosure are prepared in the above reaction Scheme 2 as follows:

A cross-coupling reaction, such as a palladium (Pd)-catalysed couplingof I-1 with a trifluoroborate (potassium salt) coupling partner offormula II-2B in the presence of an organic solvent such as toluene, andwater, a phosphine ligand such as RuPhos or Xphos, and a base such ascesium carbonate (Cs₂CO₃) can provide the cross-coupled product 1-3 inStep 1, where X is N. Compound 1-3 as prepared in this manner, can beconverted to compounds of formula I-5B by the methods of General Scheme1, steps 2-4.

The starting materials for the above reaction scheme are commerciallyavailable or can be prepared according to methods known to one skilledin the art or by methods disclosed herein. In general, the compounds ofthe disclosure are prepared in the above reaction Scheme 3 as follows:

A cross-coupling reaction, such as a nickel (Ni)-catalysed coupling ofI-1 with an alkyl bromide coupling partner of formula III-2C in thepresence of a polar solvent such as DMA, a salt such as sodium iodide(NaI), zinc (Zn), and a ligand such as pyridine-2,6-bis(carboximidamide)dihydrochloride can provide the cross-coupled product I-3 in Step 1,where X is CH or CF. Compound I-3 as prepared in this manner, can beconverted to compounds of formula I-5B by the methods of General Scheme1, steps 2-4.

In General Scheme 4, a compound of formula I-5A or I-5B is subjected tooxidation conditions, e.g., MnO₂, in a suitable solvent, such as toluene(e.g., at room temperature), or in the presence ofN,O-bis(trimethylsilyl)trifluoroacetamide, to produce a compound offormula IV-5C (i.e., formula (I′) when Z═H), followed by an optionaldeprotection step when the Z group represents a nitrogen protectinggroup, to give a compound of formula IV-5D (i.e., formula (I′)).

In General Scheme 5, a compound of formula I-5A undergoes a Claisencondensation followed by selenation/oxidation/elimination sequence togive a compound of formula V-5E. Compound formula V-5E undergoeshydrolysis followed by a copper-catalysed decarboxylation to give acompound of formula IV-5C. Subsequent deprotection, e.g., under acidicconditions and heating, provides a compound of formula IV-5D (i.e.,formula (I′) or (I″)).

For Schemes 1 to 5, X, R², R³, n, m and p are as defined herein, inparticular according to any one of Embodiments 1 to 49.

In a further embodiment, there is provided a compound of formula I-1,which is

1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.

In a further embodiment, there is provided a compound of formula (X-1)or a salt thereof,

wherein:

is a single bond or a double bond;

X is selected from CH, CF, and N;

Z is selected from hydrogen and 2,4-dimethoxybenzyl (DMB);

R^(x) is selected from hydrogen, C₁-C₆alkyl, halo (e.g., F, Cl),C₁-C₆alkoxyl, and C₃-C₈cycloalkyl;

R^(N) is selected from hydrogen and a nitrogen protecting group PG(e.g., tert-butyloxycarbonyl (Boc));

R′ is selected from hydrogen and C₁-C₆alkyl;

R¹ is selected from hydrogen and C₁-C₆alkyl;

each R² is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo,and oxo, wherein the C₁-C₆alkyl is substituted with 0-1 occurrence ofR^(2a); or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form a bridgingring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

p is 0 or 1.

In a further embodiment, there is provided a compound of formula (X) ora salt thereof,

wherein:

X is selected from CH, CF, and N;

Z is selected from hydrogen and 2,4-dimethoxybenzyl (DMB);

R^(N) is selected from hydrogen and a nitrogen protecting group PG(e.g., tert-butyloxycarbonyl (Boc))

each R² is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo,and oxo, wherein the C₁-C₆alkyl is substituted with 0-1 occurrence ofR^(2a); or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form a bridgingring;

R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;

n is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

p is 0 or 1.

In an embodiment of formula (X-1) or (X), PG is an acid labileprotecting group.

In an embodiment of formula (X-1) or (X), PG is the Boc protecting group(tert-butyloxycarbonyl).

In a further embodiment of formula (X-1) or (X), there is provided acompound or a salt thereof, selected from:

-   tert-butyl    (2S,4R)-4-((3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate;-   1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   (S)-5-methyl-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   tert-butyl    (S)-2-methyl-4-((3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate;-   tert-butyl    (2S,4R)-2-methyl-4-((3-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate;-   5-methyl-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   5-fluoro-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   tert-butyl    (2S,4R)-4-((3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate;-   (S)-5-fluoro-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   tert-butyl    (S)-4-((3-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate;-   5-chloro-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   tert-butyl    (2S,4R)-4-((3-(5-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate;-   5-methoxy-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   tert-butyl (2S,4R)-4-((3-(5-methoxy-2,4-dioxo-3,4-dihydropyrimidin-1    (2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate;-   (S)-5-methoxy-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   tert-butyl    (S)-4-((3-(5-methoxy-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate;-   (S)-5-cyclopropyl-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   tert-butyl    (S)-4-((3-(5-cyclopropyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate;-   5-cyclopropyl-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   tert-butyl    (2S,4R)-4-((3-(5-cyclopropyl-2,4-dioxo-3,4-dihydropyrimidin-1    (2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate;-   (S)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   tert-butyl    (S)-4-((3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate;-   tert-butyl    (2S,4R)-4-((3-(3-(3,4-dimethylbenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate;-   3-(3,4-dimethylbenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;-   1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;-   tert-butyl    4-((3-(3-(3,4-dimethylbenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate;-   3-(3,4-dimethylbenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;-   1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;-   tert-butyl    4-((3-(3-(3,4-dimethylbenzyl)-2,4-dioxotetrahydropyrimidin-1    (2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate;-   3-(3,4-dimethylbenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;-   1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;-   tert-butyl    (S)-4-((3-(3-(3,4-dimethylbenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate;-   (S)-3-(3,4-dimethylbenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione;    and-   (S)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.

In an embodiment of formula (X-1) or (X), the salt is selected from aHCl and TFA salt.

In a further aspect, the disclosure provides to a process for thepreparation of a compound of formula (I), (I′), (I″) or subformulaethereof, in free form or in pharmaceutically acceptable salt form,comprising the step of:

-   -   1) coupling an aryl bromide of formula (I-1) with a boraneyl        coupling partner of formula I-2A or II-2B under cross coupling        conditions, to give a compound of formula (I-3) as defined        herein.

The boraneyl coupling partner of step 1 may optionally be prepared byhydroboration of a precursor alkene, e.g., with 9-BBN.

In a further aspect, the disclosure provides a process for thepreparation of a compound of formula (I), (I′), (I″) or subformulaethereof, in free form or in pharmaceutically acceptable salt form,comprising the step of:

-   -   1) coupling an aryl bromide of formula (I-1) with an alkyl        bromide of formula (III-2C) under cross coupling conditions, to        give a compound of formula (I-3) as defined herein.

Cross coupling reaction conditions for any of the aforementioned processsteps or hereinafter involve the use of a Pd catalyst in the presence ofa phosphine ligand, such as Pd(OAc)₂ and RuPhos or Xphos, and a basesuch as cesium carbonate (Cs₂CO₃), in the presence of a suitable solventsuch as toluene, water, or a mixture thereof.

Cross coupling reaction conditions (e.g., in the case of an Sp²-Sp³coupling) may alternatively involve the use of a Ni(II) complex, such asNiCl₂(DME), ligand, such as pyridine-2,6-bis(carboximidamide)dihydrochloride, additive such as NaI, a transmetalling agent such as Znor Mn, a suitable solvent such as DMA, heating at a temperature of r.t.to 150° C., e.g., 70° C., for example, over a period of 12 hours.

In an embodiment of either process aspect described above, there isprovided the further steps of:

2) deprotecting a compound of formula (I)-3 to give a compound offormula (I)-4A or (I)-4B as defined herein;

3-a) reacting a compound of formula (I)-4A or (I)-4B under reductiveamination conditions to give a compound of formula (I)-5A or (I)-5B asdefined herein; or

3-b) reacting a compound of formula (I)-4A or (I)-4B under alkylationconditions to give a compound of formula (I)-5A or (I)-5B as definedherein; or

3-c) reacting a compound of formula (I)-4A or (I)-4B under amidecoupling conditions to give a compound of formula (I)-5A or (I)-5B asdefined herein; or

3-d) reacting a compound of formula (I)-4A or (I)-4B under acylation orsulfonylation conditions to give a compound of formula (I)-5A or (I)-5Bas defined herein; and

4) deprotecting the compound of formula (I)-5A to give a compound offormula (I) as described herein.

Reductive amination conditions for any of the aforementioned processsteps or hereinafter involve the use of a corresponding aldehyde, asuitable hydride reagent, such as NaBH(OAc)₃, a suitable solvent, suchas DMF, the reaction conducted at room temperature (r.t.).

Alkylation reaction conditions for any of the aforementioned processsteps or hereinafter involve the use of a corresponding alkyl halide,mesylate, tosylate or triflate in the presence of a suitable base, suchas DIPEA, or a carbonate base such as K₂CO₃, a polar solvent, such asDMF, the reaction conducted at a suitable temperature, such as r.t. to100° C., e.g., 80° C., optionally, under microwave.

Amide coupling reaction conditions for any of the aforementioned processsteps or hereinafter involve the use of a corresponding carboxylic acid,an activating agent, such as HATU, a suitable base, such as DIPEA orNMM, a suitable solvent, such as DMF, the reaction conducted at asuitable temperature, such as r.t., for a suitable amount of time, forexample 12 hours.

Acylation or sulfonylation reaction conditions for any of theaforementioned process steps or hereinafter involve the use of acorresponding acyl chloride or sulfonyl chloride and a base such asDIPEA or TEA, in the presence of a suitable solvent such as DCM, thereaction conducted at a suitable temperature, such as r.t.

In a further embodiment there is provided a process for the preparationof a compound of formula (I′) or (I″), comprising the step:

1) coupling an aryl bromide of formula

wherein hal is halo, preferably I, with

under cross coupling reaction conditions, to give a compound of formula

as defined herein, wherein

is a double bond or a single bond, R¹, R′, X, R², n, m, p, R^(x) are asdefined herein, e.g., according to any one of enumerated Embodiments 1to 49, PG is a nitrogen protecting group as defined herein, e.g., Boc,and R^(N) is selected from hydrogen and a nitrogen protecting group PG(e.g., tert-butyloxycarbonyl (Boc)). In an embodiment, R¹ and R′ areboth hydrogen.

Cross coupling conditions for the aforementioned process may involve theuse of copper as a catalyst, e.g., Ullmann reaction conditions. Forexample, reaction conditions may employ copper(I) iodide as a catalyst,a ligand, such as N-(2-cyanophenyl)picolinamide, a base, such as K₃PO₄,a suitable solvent, such as DMSO, heating at a temperature of r.t. to130° C., e.g., 70 to 120° C., e.g., 110° C. The reaction may be heatedover a period of 72 hours.

In a further embodiment there is provided a process for the preparationof a compound of formula (I), (I′), (I″) or subformulae thereof, in freeform or in pharmaceutically acceptable salt form according to any ofGeneral Schemes 1 to 5.

Compounds of formulae (I)-1, (X-1) and (X) as defined herein are usefulin the preparation of compounds of the disclosure, e.g., compounds offormulae (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ic″),(Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′),and (Ie). Thus, in an aspect, the disclosure relates to a compound offormula (I)-1, (X-1) or (X) or salts thereof.

In another aspect, the disclosure relates to the use of a compound offormula (I)-1, (X-1) or (X) or salts thereof in the manufacture of acompound of formulae (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), and (Ie). The disclosure further includes any variant ofthe present processes, in which an intermediate product obtainable atany stage thereof is used as starting material and the remaining stepsare carried out, or in which the starting materials are formed in situunder the reaction conditions, or in which the reaction components areused in the form of their salts or optically pure material.

Pharmaceutical Compositions

In another aspect, the disclosure provides a pharmaceutical compositioncomprising one or more compounds of described herein or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, and one or more pharmaceuticallyacceptable carriers. As used herein, the term “pharmaceuticalcomposition” refers to a compound of the disclosure, or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, together with at least onepharmaceutically acceptable carrier, in a form suitable for oral orparenteral administration.

As used herein, the term “pharmaceutically acceptable carrier” refers toa substance useful in the preparation or use of a pharmaceuticalcomposition and includes, for example, suitable diluents, solvents,dispersion media, surfactants, antioxidants, preservatives, isotonicagents, buffering agents, emulsifiers, absorption delaying agents,salts, drug stabilizers, binders, excipients, disintegration agents,lubricants, wetting agents, sweetening agents, flavoring agents, dyes,and combinations thereof, as would be known to those skilled in the art(see, for example, Remington The Science and Practice of Pharmacy,22^(nd) Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

In another aspect, the disclosure provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof, and a pharmaceutically acceptable carrier. In a furtherembodiment, the composition comprises at least two pharmaceuticallyacceptable carriers, such as those described herein. For purposes of thedisclosure, unless designated otherwise, solvates and hydrates aregenerally considered compositions. Preferably, pharmaceuticallyacceptable carriers are sterile. The pharmaceutical composition can beformulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the disclosure canbe made up in a solid form (including without limitation capsules,tablets, pills, granules, powders or suppositories), or in a liquid form(including without limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifiers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with one or more of:

a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,cellulose and/or glycine;

b) lubricants, e.g., silica, talcum, stearic acid, its magnesium orcalcium salt and/or polyethyleneglycol;

c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone;

d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt,or effervescent mixtures; and

e) absorbents, colorants, flavors and sweeteners.

In an embodiment, the pharmaceutical compositions are capsulescomprising the active ingredient only.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the disclosure in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs, solutions or soliddispersion. Compositions intended for oral use are prepared according toany method known in the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets may containthe active ingredient in admixture with nontoxic pharmaceuticallyacceptable excipients, which are suitable for the manufacture oftablets. These excipients are, for example, inert diluents, such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate orsodium phosphate; granulating and disintegrating agents, for example,corn starch, or alginic acid; binding agents, for example, starch,gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the disclosure with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The compounds of formulae (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″),(Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2),(Id-3), (Ie″), (Ie′), and (Ie) in free form or in pharmaceuticallyacceptable salt form, exhibit valuable pharmacological properties, e.g.,WIZ modulating properties or WIZ degrading properties or HbF inducingproperties e.g., as indicated in the in vitro tests as provided in theexamples, and are therefore indicated for therapy or for use as researchchemicals, e.g., as tool compounds.

Additional properties of the disclosed compounds include having goodpotency in the biological assays described herein, favorable safetyprofile, and possess favorable pharmacokinetic properties.

Diseases and Disorders

In an embodiment of the present disclosure, there is provided a compoundof the disclosure, or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, which is effectivein reducing WIZ protein expression levels and/or inducing fetalhemoglobin (HbF) expression.

The compounds of the disclosure can be used to treat one or more of thediseases or disorders described herein below. In one embodiment, thedisease or disorder is affected by the reduction of WIZ proteinexpression levels and/or induction of fetal hemoglobin proteinexpression levels. In another embodiment, the disease or disorder is ahemoglobinopathy, e.g., beta hemoglobinopathy, including sickle celldisease (SCD) and beta-thalassemia.

Methods of Use

All the aforementioned embodiments and embodiments hereinafter relatingto the methods of reducing WIZ protein expression levels and/or inducingfetal hemoglobin (HbF) expression are equally applicable to:

A compound of the disclosure, or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use ina method of reducing WIZ protein expression levels and/or inducing fetalhemoglobin (HbF) expression;

A compound of the disclosure, or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use inthe treatment of the aforementioned diseases or disorders according tothe present disclosure;

Use of a compound of the disclosure, or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, inthe treatment of the aforementioned diseases or disorders according tothe present disclosure; and

A pharmaceutical composition comprising a compound of the disclosure, ora pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the treatment of theaforementioned diseases or disorders according to the presentdisclosure.

Having regard to their activity as WIZ modulators or degraders,compounds of formulae (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), and (Ie) in free or pharmaceutically acceptable salt form,are useful in the treatment of conditions which may be treated bymodulation of WIZ protein expression levels, reduction of WIZ proteinexpression levels, or induction of fetal hemoglobin (HbF), such as in ablood disorder, for example an inherited blood disorder, e.g., sicklecell disease, or beta-thalassemia.

In one aspect, the disclosure provides a method of treating orpreventing a disease or disorder in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′),(Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id),(Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In another aspect, the disclosure provides a method of treating orpreventing a disorder that is affected by the reduction of WIZ proteinlevels, in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id ″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of inhibiting WIZprotein expression in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of degrading WIZprotein in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of inhibiting,reducing, or eliminating the activity of WIZ protein or WIZ proteinexpression, the method comprising administering to the subject acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of inducing orpromoting fetal hemoglobin in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″),(Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2),(Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of reactivatingfetal hemoglobin production or expression in a subject in need thereof,the method comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′),(Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id),(Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In another aspect, the disclosure provides a method of increasing fetalhemoglobin expression in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″),(Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2),(Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of treating ahemoglobinopathy, e.g., a beta-hemoglobinopathy, in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a compound of (I″), (I′), (I),(Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id ″),(Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of treating a sicklecell disease in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a method of treatingbeta-thalassemia in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In an embodiment, the beta-thalassemia major or intermedia is the resultof homozygous null or compound heterozygous mutations resulting withbeta-globin deficiency and the phenotypic complications ofbeta-thalassemia, whether transfusion-dependent or not.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of treating orpreventing a disease or disorder in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′),(Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id),(Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of treating orpreventing a disorder that is affected by the reduction of WIZ proteinlevels, in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of inhibiting WIZprotein expression in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id ″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of degrading WIZprotein in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of inhibiting,reducing, or eliminating the activity of WIZ protein or WIZ proteinexpression, the method comprising administering to the subject acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of inducing orpromoting fetal hemoglobin in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia),(Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1),(Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of reactivatingfetal hemoglobin production or expression in a subject in need thereof,the method comprising administering to the subject a therapeuticallyeffective amount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′),(Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id),(Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of increasingfetal hemoglobin expression in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia),(Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1),(Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of treating ahemoglobinopathy, e.g., a beta-hemoglobinopathy, in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a compound of formula (I″), (I′),(I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″),(Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of treating asickle cell disease in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In another aspect, the disclosure provides a compound of formula (I″),(I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic),(Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof for use in a method of treatingbeta-thalassemia in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof.

In an embodiment, the beta-thalassemia major or intermedia is the resultof homozygous null or compound heterozygous mutations resulting withbeta-globin deficiency and the phenotypic complications ofbeta-thalassemia, whether transfusion-dependent or not.

Dosage

The pharmaceutical composition or combination of the disclosure can bein unit dosage of about 1-1000 mg of active ingredient(s) for a subjectof about 50-70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mgor about 0.5-100 mg, or about 1-50 mg of active ingredients. Thetherapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thedisclosure can be applied in vitro in the form of solutions, e.g.,aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10-3 molar and10-9 molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The activity of a compound according to the disclosure can be assessedby the in vitro methods described in the Examples.

Combination Therapy

In another aspect, the disclosure provides a pharmaceutical combinationcomprising a compound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia),(Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1),(Id-2), (Id-3), (Ie″), (Ie′), or (Ie), or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, andone or more additional therapeutic agent(s) for simultaneous, separateor sequential use in therapy. In an embodiment, the additionaltherapeutic agent is a myelosuppressive agent, such as hydroxyurea.

Combination therapy includes the administration of the subject compoundsin further combination with other biologically active ingredients (suchas, but not limited to, a second and different antineoplastic agent or atherapeutic agent that targets HbF or another cancer target) andnon-drug therapies (such as, but not limited to, surgery or radiationtreatment). For instance, the compounds of the application can be usedin combination with other pharmaceutically active compounds, preferablycompounds that are able to enhance the effect of the compounds of theapplication.

The compound of the disclosure may be administered either simultaneouslywith, or before or after, one or more other therapeutic agents. Thecompound of the disclosure may be administered separately, by the sameor different route of administration, or together in the samepharmaceutical composition as the other agents. A therapeutic agent is,for example, a chemical compound, peptide, antibody, antibody fragmentor nucleic acid, which is therapeutically active or enhances thetherapeutic activity when administered to a patient in combination witha compound of the disclosure. Thus, in one embodiment, the disclosureprovides a combination comprising a therapeutically effective amount ofa compound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof and one or moreadditional therapeutically active agents.

In one embodiment, the disclosure provides a product comprising acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie), and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a disease orcondition modulated by WIZ. Products provided as a combined preparationinclude a composition comprising the compound of formula (I″), (I′),(I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″),(Id′), (Id), (Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), and theother therapeutic agent(s) together in the same pharmaceuticalcomposition, or the compound of formula (I″), (I′), (I), (Ia″), (Ia′),(Ia), (Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id),(Id-1), (Id-2), (Id-3), (Ie″), (Ie′), or (Ie), and the other therapeuticagent(s) in separate form, e.g., in the form of a kit.

In one embodiment, the disclosure provides a pharmaceutical compositioncomprising a compound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia),(Ib″), (Ib′), (Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1),(Id-2), (Id-3), (Ie″), (Ie′), or (Ie), and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable carrier, as described above.

In one embodiment, the disclosure provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I″), (I′), (I), (Ia″), (Ia′), (Ia), (Ib″), (Ib′),(Ib), (Ic″), (Ic′), (Ic), (Id″), (Id′), (Id), (Id-1), (Id-2), (Id-3),(Ie″), (Ie′), or (Ie). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the disclosure may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the disclosure typically comprises directions for administration.

In the combination therapies of the disclosure, the compound of thedisclosure and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the disclosure and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g., in the case of a kit comprisingthe compound of the disclosure and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.,during sequential administration of the compound of the disclosure andthe other therapeutic agent.

Preparation of Compounds

It is understood that in the following description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such combinations result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocesses described below, the functional groups of intermediatecompounds may need to be protected by suitable protecting groups. Suchfunctional groups include hydroxy, phenol, amino and carboxylic acid.

Suitable protecting groups for hydroxy or phenol include trialkylsilylor diarylalkylsilyl (e.g., t-butyldimethylsilyl, t-butyldiphenylsilyl ortrimethylsilyl), tetrahydropyranyl, benzyl, substituted benzyl, methyl,and the like. Suitable protecting groups for amino, amidino andguanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like.Suitable protecting groups for carboxylic acid include alkyl, aryl orarylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are well-known to those skilled in the art and asdescribed herein. The use of protecting groups is described in detail inJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973; T. W. Greene and P. G. M. Wuts, “Greene'sProtective Groups in Organic Synthesis”, Fourth Edition, Wiley, New York2007; P. J. Kocienski, “Protecting Groups”, Third Edition, Georg ThiemeVerlag, Stuttgart and New York 2005; and in “Methoden der organischenChemie” (Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume15/I, Georg Thieme Verlag, Stuttgart 1974.

The protecting group may also be a polymer resin, such as a Wang resinor a 2-chlorotrityl-chloride resin.

The following reaction schemes illustrate methods to make compounds ofthis disclosure. It is understood that one skilled in the art would beable to make these compounds by similar methods or by methods known toone skilled in the art. In general, starting components and reagents maybe obtained from sources such as Sigma Aldrich, Lancaster Synthesis,Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, Strem,other commercial vendors, or synthesized according to sources known tothose skilled in the art, or prepared as described in this disclosure.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Proton nuclear magnetic resonance (NMR) spectrawere obtained on either Bruker Avance spectrometer or Varian Oxford 400MHz spectrometer unless otherwise noted. Spectra are given in ppm (δ)and coupling constants, J, are reported in Hertz. Tetramethylsilane(TMS) was used as an internal standard. Chemical shifts are reported inppm relative to dimethyl sulfoxide (δ 2.50), methanol (δ 3.31),chloroform (δ 7.26) or other solvent as indicated in NMR spectral data.A small amount of the dry sample (2-5 mg) is dissolved in an appropriatedeuterated solvent (1 mL). The chemical names were generated usingChemBioDraw Ultra v12 from CambridgeSoft.

Mass spectra (ESI-MS) were collected using a Waters System (Acquity UPLCand a Micromass ZQ mass spectrometer) or Agilent-1260 Infinity (6120Quadrupole); all masses reported are the m/z of the protonated parentions unless recorded otherwise. The sample was dissolved in a suitablesolvent such as MeCN, DMSO, or MeOH and was injected directly into thecolumn using an automated sample handler. The analysis is performed onWaters Acquity UPLC system (Column: Waters Acquity UPLC BEH C18 1.7 μm,2.1×30 mm; Flow rate: 1 mL/min; 55° C. (column temperature); Solvent A:0.05% formic acid in water, Solvent B: 0.04% formic acid in MeOH;gradient 95% Solvent A from 0 to 0.10 min; 95% Solvent A to 20% SolventA from 0.10 to 0.50 min; 20% Solvent A to 5% Solvent A from 0.50 to 0.60min; hold at 5% Solvent A from 0.6 min to 0.8 min; 5% Solvent A to 95%Solvent A from 0.80 to 0.90 min; and hold 95% Solvent A from 0.90 to1.15 min.

Abbreviations

-   ACN acetonitrile-   AcOH acetic acid-   AIBN azobisisobutyronitrile-   aq. aqueous-   B₂pin₂ bis(pinacolato)diboron-   9-BBN 9-borabicyclo[3.3.1]nonane-   Boc₂O di-tert-butyl dicarbonate-   Bn benzyl-   BnBr benzyl bromide-   br broad-   d doublet-   dd doublet of doublets-   ddd doublet of doublet of doublets-   ddq doublet of doublet of quartets-   ddt doublet of doublet of triplets-   dq doublet of quartets-   dt doublet of triplets-   dtbbpy 4,4′-di-tert-butyl-2,2′-dipyridyl-   dtd doublet of triplet of doublets-   Cs2CO₃ cesium carbonate-   DCE 1,2-dichloroethane-   DCM dichloromethane-   DHP dihydropyran-   DIBAL-H diisobutylaluminium hydride-   DIPEA (DIEA) diisopropylethylamine-   DIPEA N,N-diisopropylethylamine-   DMA N,N-dimethylacetamide-   DMAP 4-dimethylaminopyridine-   DMB 2,4-dimethoxybenzyl-   DME 1,2-dimethoxyethane-   DMF N,N-dimethylformamide-   DMP Dess-Martin periodinane or    1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one-   DMSO dimethylsulfoxide-   EC₅₀ half maximal effective concentration-   ELSD evaporative light scattering detector-   EtOH ethanol-   Et₂O diethyl ether-   Et₃N triethylamine-   EtOAc ethyl acetate-   HATU    1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HCl hydrogen chloride-   hept heptet-   HPLC high performance liquid chromatography-   h or hr hour-   HRMS high resolution mass spectrometry-   g gram-   g/min gram per minute-   IC₅₀ half maximal inhibitory concentration-   IPA (iPrOH) isopropyl alcohol-   Ir[(dF(CF₃)ppy)₂dtbbpy]PF₆    [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III)    hexafluorophosphate-   K₂CO₃ potassium carbonate-   KI potassium iodide-   KOAc potassium Acetate-   K₃PO₄ tripotassium phosphate-   LCMS liquid chromatography mass spectrometry-   LDA lithium diisopropylamide-   m multiplet-   MeCN acetonitrile-   MeOH methanol-   mg milligram-   MHz megahertz-   min minutes-   mL milliliter-   mmol millimole-   M molar-   MS mass spectrometry-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   NaBH(OAc)₃ sodium triacetoxyborohydride-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NMM N-methylmorpholine-   NMP N-methyl-2-pyrrolidone-   NMR nuclear magnetic resonance-   on overnight-   Pd/C palladium on carbon-   PdCl₂(dppf).DCM    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex    with dichloromethane-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)-   PMB para-methoxybenzyl-   q quartet-   qd quartet of doublets-   quint quintet-   quintd quintet of doublets-   rbf round bottom flask-   RockPhos G3 Pd    [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2-aminobiphenyl)]palladium(II)    methanesulfonate-   rt or r.t. room temperature-   Rt retention time-   RuPhos    dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphane-   s singlet-   SEM 2-(trimethylsilyl)ethoxymethyl-   SnBu₃ tributyltin-   t triplet-   td triplet of doublets-   tdd triplet of doublet of doublets-   TBAI tetrabutylammonium iodide-   TEA (NEt₃) triethylamine-   TFA trifluoroacetic acid-   TfOH triflic Acid-   THF tetrahydrofuran-   THP tetrahydropyran-   TMP 2,2,6,6-tetramethylpiperidine-   Ts tosyl-   tt triplet of triplets-   ttd triplet of triplet of doublets-   TLC thin-layer chromatography-   UPLC ultra-Performance liquid Chromatography-   XPhos Pd G2    chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)-   μW or uW microwave

Preparation of Intermediates Preparation of3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl(3-((2,4-dimethoxybenzyl)amino)-3-oxopropyl)carbamate.

To a solution of 3-((tert-butoxycarbonyl)amino)propanoic acid (200 g,1.06 mol, 1.00 eq) in DCM (1200 mL) was added CDI (189 g, 1.16 mol, 1.10eq). The reaction mixture was stirred at 20° C. for 2 h. The reactionmixture was slowly added to a solution of(2,4-dimethoxyphenyl)methanamine (212 g, 1.27 mol, 191 mL, 1.20 eq) andDMAP (12.9 g, 106 mmol, 0.10 eq) in DCM (1000 mL). The solution wasstirred at 20° C. for 12 h. The reaction mixture was slowly poured intowater (2 L) and stirred at rt for 10 min. The organic phase wasseparated and the water phase was extracted with DCM (800 mL×2). Thecombined organic phase was washed with brine (1 L×2) and dried overNa₂SO₄, filtered and concentrated. The crude material was purified bysilica gel chromatography (eluted with 50:1 to 2:1 petroleum ether:ethylacetate) to give tert-butyl(3-((2,4-dimethoxybenzyl)amino)-3-oxopropyl)carbamate (210 g, 621 mmol,59% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.06 (t, J=5.6Hz, 1H), 7.08-7.01 (m, 1H), 6.72 (br t, J=5.3 Hz, 1H), 6.55-6.51 (m,1H), 6.46 (dd, J=2.4, 8.4 Hz, 1H), 4.13 (d, J=5.6 Hz, 2H), 3.77 (s, 3H),3.73 (s, 3H), 3.13 (q, J=7.0 Hz, 2H), 2.28 (t, J=7.3 Hz, 2H), 1.37 (s,9H).

Step 2. 3-amino-N-(2,4-dimethoxybenzyl)propanamide hydrochloride

To a solution of tert-butyl(3-((2,4-dimethoxybenzyl)amino)-3-oxopropyl)carbamate (210 g, 621 mmol,1.00 eq) in DCM (1000 mL) was added HCl/dioxane (4 M, 1000 mL, 6.45 eq)and the solution was stirred at 20° C. for 5 h. The reaction mixture wasconcentrated to give 3-amino-N-(2,4-dimethoxybenzyl)propanamidehydrochloride (180 g, crude, HCl salt) as a white solid which was usedin the next step without further purification. ¹H NMR (400 MHz, DMSO-d6)δ 8.38 (br t, J=5.6 Hz, 1H), 8.07 (br s, 3H), 7.08 (d, J=8.3 Hz, 1H),6.53 (d, J=2.4 Hz, 1H), 6.46 (dd, J=2.4, 8.3 Hz, 1H), 4.15 (d, J=5.6 Hz,2H), 3.75 (d, J=15.6 Hz, 6H), 2.96 (sxt, J=6.3 Hz, 2H), 2.59-2.52 (m,2H).

Step 3. 3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

To a mixture of 3-amino-N-(2,4-dimethoxybenzyl)propanamide hydrochloride(180 g, 655 mmol, 1.00 eq) and DIPEA (212 g, 1.64 mol, 285 mL, 2.50 eq)in DCE (1200 mL) was added CDI (127 g, 786 mmol, 1.20 eq) at 0° C. Themixture was stirred at 0° C. for 0.5 h, then heated to 100° C. andstirred for 12 h. The reaction mixture was slowly poured into water(1000 mL) and stirred at 20° C. for 20 min. The organic phase wasseparated and the water phase was extracted with DCM (500 mL*2). Thecombined organic phases were washed with brine (500 mL*2), dried overNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (45:1 to 0:1 petroleum ether:ethyl acetate) to give3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (120 g, 454mmol, 69% yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 6.99 (d,J=8.3 Hz, 1H), 6.48-6.37 (m, 2H), 5.79 (br s, 1H), 4.93 (s, 2H), 3.80(d, J=15.3 Hz, 6H), 3.41 (dt, J=2.6, 6.8 Hz, 2H), 2.76 (t, J=6.8 Hz,2H).

Preparation of potassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborate

Step 1.(((3R)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-ium-1-yl)methyl)trifluoroborate

To a solution of potassium (bromomethyl)trifluoroborate (2.00 g, 9.96mmol) in THF (10 mL) was added tert-butyl(R)-2-methylpiperazine-1-carboxylate (2.09 g, 15.7 mmol). The reactionmixture was stirred at 80° C. for 16 h. The reaction mixture wasfiltered and the filter cake was washed with THF (2×10 mL), and thefilter cake was collected and dried to give(((3R)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-ium-1-yl)methyl)trifluoroborate(4.3 g, crude) as a white solid. The crude was used in the next stepwithout any other purification. ¹H NMR (400 MHz, DMSO-d6) δ 8.45-8.44(m, 1H), 4.31-2.92 (m, 1H), 3.87-3.82 (m, 1H), 3.67-3.54 (m, 1H),3.27-3.04 (m, 2H), 2.99-2.77 (m, 2H), 1.99 (br s, 2H), 1.83-1.70 (m,1H), 1.50-1.37 (m, 9H), 1.21 (br d, J=7.2 Hz, 3H).

Step 2. potassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborate

To a solution of(((3R)-4-(tert-butoxycarbonyl)-3-methylpiperazin-1-ium-1-yl)methyl)trifluoroborate(4.3 g, crude) in acetone (20 mL) was added K₂CO₃ (2.10 g, 15.2 mmol)and the reaction mixture was stirred at 25° C. for 16 h. The reactionmixture was filtered and the filter cake was washed with acetone (2×10mL), and the filtrate was concentrated to give potassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborate(1.1 g, crude) as a white solid. The crude material was used in the nextstep without any other purification. ¹H NMR (400 MHz, DMSO-d6) δ 4.09(br s, 1H), 3.79-3.60 (m, 1H), 3.51-3.21 (m, 1H), 2.98 (br s, 3H),1.71-1.46 (m, 2H), 1.39 (s, 9H), 1.15 (d, J=7.2 Hz, 3H).

Additional Borate Salts Prepared by the Method Above:

The borate salts in the following table were prepared by the method ofpotassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborateusing the appropriate commercially available piperazine in step 1 exceptwhere noted.

Structure Starting material

tert-butyl (S)-2-ethylpiperazine-1- carboxylate potassium (S)-((4-(tert-butoxycarbonyl)-3-ethylpiperazin- 1-yl)methyl)trifluoroborate

tert-butyl (S)-2-isopropylpiperazine-1- carboxylate potassium(S)-((4-(tert- butoxycarbonyl)-3-isopropylpiperazin-1-yl)methyl)trifluoroborate

tert-butyl 2,2-dimethylpiperazine-1- carboxylate potassium((4-(tert-butoxycarbonyl)- 3,3-dimethylpiperazin-1-yl)methyl)trifluoroborate

tert-butyl (1R,5S)-3,8- diazabicyclo[3.2.1]octane-8-carboxylatepotassium (((1R,5S)-8-(tert- butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl) trifluoroborate

tert-butyl (1R,4R)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylatepotassium (((1R,4R)-5-(tert- butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl) trifluoroborate

tert-butyl (1S,4S)-2,5- diazabicyclo[2.2.1]heptane-2-carboxylatepotassium (((1S,4S)-5-(tert- butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl) trifluoroborate

1-(3-methylbutan-2-yl)piperazine potassium trifluoro((4-(3-methylbutan-2-yl)piperazin-1-yl)methyl)borate

tert-butyl 1,4-diazepane-1-carboxylate potassium((4-(tert-butoxycarbonyl)- 1,4-diazepan-1-yl)methyl) trifluoroborate

1-(cyclohexylmethyl)piperazin-2-one [see RSC Advances, 2018, 8, 11163-11176] potassium ((4-(cyclohexylmethyl)-3-oxopiperazin-1-yl)methyl)trifluoroborate

1-(2-cyclohexylethyl)piperazin-2-one [see J. Med. Chem. 1990, 33,2590-2595] potassium ((4-(2-cyclohexylethyl)-3-oxopiperazin-1-yl)methyl)trifluoroborate

(R)-1-(cyclohexylmethyl)-2- (methoxymethyl)piperazine hydrochloride[vide infra] potassium (R)-((4-(cyclohexylmethyl)-3-(methoxymethyl)piperazin-1- yl)methyl)trifluoroborate

(R)-1-isobutyl-2- (methoxymethyl)piperazine hydrochloride [vide infra]potassium (R)-trifluoro((4-isobutyl-3- (methoxymethyl)piperazin-1-yl)methyl)borate

(R)-1-(cyclohexylmethyl)-2- (difluoromethyl)piperazine hydrochloride[vide infra] potassium (R)-((4-(cyclohexylmethyl)-3-(difluoromethyl)piperazin-1- yl)methyl)trifluoroborate

(R)-2-(difluoromethyl)-1-isobutylpiperazine hydrochloride [vide infra]potassium (R)-((3-(difluoromethyl)-4- isobutylpiperazin-1-yl)methyl)trifluoroborate

1-(3,3,3-trifluoro-2,2- dimethylpropyl)piperazine hydrochloride [videinfra] potassium trifluoro((4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazin-1-yl) methyl)borate

(S)-octahydropyrrolo[1,2-a]pyrazine potassium (S)-trifluoro((hexahydro-pyrrolo[1,2-a]pyrazin-2(1H)- yl)methyl)borate

(R)-octahydropyrrolo[1,2-a]pyrazine potassium (R)-trifluoro((hexahydro-pyrrolo[1,2-a]pyrazin-2(1H)- yl)methyl)borate

(S)-octahydro-2H-pyrido[1,2-a]pyrazine potassium(S)-trifluoro((octahydro- 2H-pyrido[1,2-a]pyrazin- 2-yl)methyl)borate

(R)-octahydropyrazino[2,1-c][1,4]oxazine potassium (R)-trifluoro((hexahydropyrazino [2,1-c][1,4]oxazin-8(1H)-yl) methyl)borate

(S)-octahydropyrazino[2,1-c][1,4]oxazine potassium (S)-trifluoro((hexahydropyrazino[2,1-c] [1,4]oxazin-8(1H)-yl)methyl)borate

Preparation of (R)-1-(cyclohexylmethyl)-2-(methoxymethyl)piperazinehydrochloride

Step 1. tert-butyl(R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate

To a stirred solution of tert-butyl(R)-3-(hydroxymethyl)piperazine-1-carboxylate (6.0 g, 27.7 mmol) andcyclohexanecarbaldehyde (4.6 g, 41.6 mmol) dissolved in DCM (70 mL) wasadded Et₃N (11.7 mL, 83.2 mmol). The reaction mixture was stirred for 30min at rt and then sodium triacetoxy borohydride (11.7 g, 55.5 mmol) wasadded in portions at 0° C. The reaction mixture was allowed to stirredat rt for 16 h. The reaction was diluted with DCM and water and theorganic layer was dried over Na₂SO₄, filtered and and concentrated. Thecrude compound was purified by silica gel chromotography (eluting with10-20% EtOAc in hexanes) to afford tert-butyl(R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (4.2g, 13.4 mmol, 48% yield). LCMS [M+H-tBu]⁺: 257.2.

Step 2. tert-butyl(R)-4-(cyclohexylmethyl)-3-(methoxymethyl)piperazine-1-carboxylate

To a stirred solution of tert-butyl(R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (0.70g, 2.2 mmol) in DMF (10 mL) cooled to 0° C. was added NaH (0.13 g, 3.36mmol) under an inert atmosphere. The reaction mixture was stirred at 0°C. for 30 min and then Mel (0.47 g, 3.36 mmol) was added at 0° C. Thereaction was diluted with EtOAc and water and the organic layer wasdried over Na₂SO₄, filtered and and concentrated. The crude compound waspurified by silica gel chromotography (eluting with 10-20% EtOAc inhexanes) to afford tert-butyl(R)-4-(cyclohexylmethyl)-3-(methoxymethyl)piperazine-1-carboxylate (0.45g, 1.37 mmol, 61%). LCMS [M+H]⁺: 327.1

Step 3. (R)-1-(cyclohexylmethyl)-2-(methoxymethyl)piperazinehydrochloride

To a stirred solution of tert-butyl(R)-4-(cyclohexylmethyl)-3-(methoxymethyl)piperazine-1-carboxylate (0.45g, 1.37 mmol) in DCM (7.0 mL) cooled to 0° C. was added a solution ofHCl (4.0 M in dioxane, 4.0 mL). The reaction mixture was stirred at rtfor 3 h and then concentrated. The crude compound was washed withdiethyl ether to afford(R)-1-(cyclohexylmethyl)-2-(methoxymethyl)piperazine hydrochloride (0.40g, crude). LCMS [M+H]⁺: 227.1.

Preparation of (R)-1-isobutyl-2-(methoxymethyl)piperazine hydrochloride

Prepared by the method of(R)-1-(cyclohexylmethyl)-2-(methoxymethyl)piperazine hydrochloride,using isobutyraldehyde in step 1. LCMS [M+H]+: 187.1.

Preparation of (R)-1-(cyclohexylmethyl)-2-(difluoromethyl)piperazinehydrochloride

Step 1. tert-butyl(R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate

To a stirred solution of tert-butyl(R)-3-(hydroxymethyl)piperazine-1-carboxylate (6.0 g, 27.75 mmol) andcyclohexanecarbaldehyde (4.6 g, 41.62 mmol) in DCM (70 mL) was addedEt₃N (11.69 mL, 83.25 mmol). The reaction mixture was stirred for 30 minat rt. Sodium triacetoxy borohydride (11.7 g, 55.50 mmol) was then addedslowly at 0° C. The reaction mixture was stirred at rt for 16 h. Aftercompletion, the reaction was diluted with DCM and water and the organiclayer was dried over Na₂SO₄, filtered and and concentrated. The crudecompound was purified by silica gel chromotography (eluting with 10-20%EtOAc in hexanes) to afford tert-butyl(R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (4.2g, 13.44 mmol, 48% yield). LCMS [M+H-tBu]⁺: 257.2.

Step 2. tert-butyl(R)-4-(cyclohexylmethyl)-3-formylpiperazine-1-carboxylate

To a stirred solution of oxalyl chloride (2.04 mL, 24.0 mmol) in DCM (25mL) at −78° C. was added DMSO (3.41 mL, 48.0 mmol) dropwise under aninert atmosphere. The reaction mixture was stirred at −78° C. for 15 minand then a solution of tert-butyl(R)-4-(cyclohexylmethyl)-3-(hydroxymethyl)piperazine-1-carboxylate (2.5g, 8.0 mmol) in DCM (5.0 mL) was added dropwise at −78° C. The reactionmixture was stirred at −78° C. for 1 h and Et₃N (11.24 mL, 80.01 mmol)was added slowly. The reaction mixture was stirred at −78° C. for 1 hand allowed to warm to rt. The reaction was diluted with DCM and waterand the organic layer was dried over Na₂SO₄, filtered and andconcentrated to afford crude tert-butyl(R)-4-(cyclohexylmethyl)-3-formylpiperazine-1-carboxylate (2.7 g,crude). LCMS [M+H]+: 311.1.

Step 3. tert-butyl(R)-4-(cyclohexylmethyl)-3-(difluoromethyl)piperazine-1-carboxylate

To a stirred solution of tert-butyl(R)-4-(cyclohexylmethyl)-3-formylpiperazine-1-carboxylate (2.7 g, 8.69mmol) in DCM (30 mL) at 0° C. was added DAST (2.29 mL, 17.4 mmol) underan inert atmosphere. The reaction mixture was stirred at 0° C. for 2 h.After completion, the reaction was quenched with saturated aqueousNaHCO₃ solution and diluted with DCM. The organic layer was dried overNa₂SO₄, filtered and and concentrated. The crude compound was purifiedby silica gel chromotography (eluting with 10-15% EtOAc in hexanes) toafford tert-butyl(R)-4-(cyclohexylmethyl)-3-(difluoromethyl)piperazine-1-carboxylate(0.41 g, 1.23 mmol, 14% yield). LCMS [M+H]+: 333.5.

Step 4. (R)-1-(cyclohexylmethyl)-2-(difluoromethyl)piperazinehydrochloride

To a stirred solution of tert-butyl(R)-4-(cyclohexylmethyl)-3-(difluoromethyl)piperazine-1-carboxylate(0.41 g, 1.2 mmol) in DCM (7.0 mL) at 0° C. was added a solution of HClin dioxane (4.0 M, 4.0 mL). The reaction mixture was stirred at rt for 3h. After completion, the mixture was concentrated and the crude compoundwas washed with diethyl ether to afford(R)-1-(cyclohexylmethyl)-2-(difluoromethyl)piperazine hydrochloride(0.33 g, 1.2 mmol, 100% yield). LCMS [M+H]⁺: 232.9.

Preparation of 1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazinehydrochloride

Step 1. tert-butyl4-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperazine-1-carboxylate

To a stirred solution of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (1.0g, 6.4 mmol) in DMF (15 mL) was added DIPEA (3.35 mL, 19.2 mmol)followed by HATU (3.65 g, 9.60 mmol) under inert atmosphere. Thereaction mixture was stirred at rt for 15 min. After 15 min tert-butylpiperazine-1-carboxylate (1.43 g, 7.68 mmol) was added and the mixturewas stirred at rt for 16 h. The reaction was poured into cold water andthe precipitate was filtered and dried under vacuum to afford crudetert-butyl4-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperazine-1-carboxylate (1.0g, 3.08, 48% yield). LCMS [M+H-tBu]⁺: 269.1.

Step 2. tert-butyl4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(3,3,3-trifluoro-2,2-dimethylpropanoyl)piperazine-1-carboxylate (1.0g, 3.08 mmol) in THF (15 mL) at 0° C. was added BH₃DMS (15.4 mL, 30.8mmol, 1M in THF) under inert atmosphere. The reaction mixture was thenstirred at 50° C. for 16 h. The reaction was quenched with MeOH andconcentrate. The residue was dissolved in DCM and washed sequentiallywith a solution of aqueous 2M NaHCO₃ and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The crude compound waspurified by silica gel chromotography (eluting with 10-12% EtOAc inhexanes) to afford tert-butyl4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-carboxylate (0.5 g,1.61 mmol, 52% yield). LCMS [M+H-tBu]⁺: 254.9.

Step 3. 1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine hydrochloride

To stirred solution of tert-butyl4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine-1-carboxylate (500 mg,1.61 mmol) in DCM (7 mL) was added 4M HCl in dioxane (3 mL) and themixture was stirred at rt for 2 h. The mixture was concentrated and theresidue was washed with diethyl ether to afford1-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazine hydrochloride (500 mg,crude). LCMS [M+H]⁺: 211.2.

Preparation of (3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl4-methylbenzenesulfonate.

Step 1. 3-iodopyrazolo[1,5-a]pyridine-5-carbaldehyde

NIS (1.4 g, 5.92 mmol) was added to a solution ofpyrazolo[1,5-a]pyridine-5-carbaldehyde (790 mg, 5.41 mmol) in DMF (10mL) at 0° C. The mixture was then stirred at rt for 8 h. Aftercompletion, the reaction was quenched with water and the solid thatprecipitated was collected by filtration and dried under vacuum toafford 3-iodopyrazolo[1,5-a]pyridine-5-carbaldehyde (1.2 g, 4.4 mmol,81% yield). LCMS [M+H]⁺: 273.0.

Step 2. (3-iodopyrazolo[1,5-a]pyridin-5-yl)methanol

To a stirred solution of 3-iodopyrazolo[1,5-a]pyridine-5-carbaldehyde(1.2 g, 4.40 mmol) in MeOH:THF (2:1) (10 mL) was added NaBH₄ (250 mg,6.60 mmol) at 0° C. The reaction mixture was stirred for 1 h and thenconcentrated. The residue was diluted with water and extracted with DCM.The organic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford (3-iodopyrazolo[1,5-a]pyridin-5-yl)methanol (800mg, crude). LCMS [M+H]⁺: 274.7.

Step 3. (3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl4-methylbenzenesulfonate

To a stirred solution of (3-iodopyrazolo[1,5-a]pyridin-5-yl)methanol(700 mg, 2.55 mmol) in DCM (10 mL) at 0° C. was added TEA (0.8 mL, 3.66mmol). The mixture was stirred for 10 min and then tosyl chloride (610mg, 3.06 mmol) and DMAP (38 mg, 0.25 mmol) were added. The reaction wasstirred at rt for 1 h. The mixture was then diluted with DCM and waterand the organic layer was dried over Na₂SO₄, filtered and concentratedto afford (3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl4-methylbenzenesulfonate (1.0 g, crude). The crude material was usedwithout further purification.

Preparation of trans-3-methoxycyclobutane-1-carbaldehyde

To a solution of trans-3-methoxycyclobutylmethanol [see WO2021/124172,2021, A1] (0.30 g, 2.6 mmol), 1.0 eq) in DCM (15 mL) at 0° C. was addedDMP (1.2 g, 2.8 mmol, 1.1 eq). The reaction mixture was stirred at 0° C.for 2 h. The reaction mixture was then concentrated. The crude materialwas purified by neutral alumina chromatography (eluted with 15% EtOAc inhexane) to give trans-3-methoxycyclobutane-1-carbaldehyde (0.21 g, 1.8mmol, 71% yield) as a colorless oil.

Preparation of cis-3-methoxycyclobutane-1-carbaldehyde

To a solution of cis-3-methoxycyclobutylmethanol [see WO2021/124172,2021, A1] (0.10 g, 0.86 mmol, 1.0 eq) in DCM (7 mL) at 0° C. was addedDMP (0.40 g, 0.94 mmol, 1.1 eq). The reaction mixture was stirred at 0°C. for 2 h. The reaction mixture was then concentrated. The crudematerial was diluted with Et₂O (10 mL) and filtered through celite,washing with additional Et₂O. The filtrate was concentrated to givecrude cis-3-methoxycyclobutane-1-carbaldehyde (0.12 g, 1.1 mmol). Thecrude material was used in the next step without any other purification.

Preparation of (R)-3,3-difluorocyclopentane-1-carbaldehyde

To a solution of (R)-(3,3-difluorocyclopentyl)methanol (0.230 g, 1.69mmol), 1.0 eq) in DCM (5 mL) at 0° C. was added DMP (0.788 g, 1.86 mmol,1.1 eq). The reaction mixture was stirred at rt for 2 h. The reactionmixture was then concentrated. The crude material was diluted with EtOAc(10 mL) and filtered through celite. The filtrate was washed with water,dried over MgSO₄, filtered and concentrated. The crude material waspurified by neutral alumina chromatography (eluted with 20% EtOAc inhexane) to give (R)-3,3-difluorocyclopentane-1-carbaldehyde (0.13 g,0.97 mmol, 57% yield) as a yellow oil.

Preparation of (S)-3,3-difluorocyclopentane-1-carbaldehyde

To a solution of (S)-(3,3-difluorocyclopentyl)methanol (0.170 g, 1.24mmol), 1.0 eq) in DCM (10 mL) at 0° C. was added DMP (0.582 g, 1.37mmol, 1.1 eq). The reaction mixture was stirred at rt for 2 h. Thereaction mixture was then concentrated. The crude material was purifiedby neutral alumina chromatography (eluted with 20% EtOAc in hexane) togive (S)-3,3-difluorocyclopentane-1-carbaldehyde (0.15 g) as a colorlessoil.

Preparation of (1r,3R,4S)-3,4-difluorocyclopentane-1-carbaldehyde

To a solution of ((1r,3R,4S)-3,4-difluorocyclopentyl)methanol [seeEP2275414, 2011, A1] (0.170 g, 1.24 mmol), 1.0 eq) in DCM (10 mL) at 0°C. was added DMP (1.58 g, 3.74 mmol, 3.0 eq). The reaction mixture wasstirred at rt for 2 h. The reaction mixture was then diluted with Et₂Oand filtered through neutral alumina, washing with additional Et₂O. Thefiltrate containing crude(1r,3R,4S)-3,4-difluorocyclopentane-1-carbaldehyde was used in the nextstep without any other purification.

Preparation of 2-oxaspiro[3.3]heptane-6-carbaldehyde

To a solution of (2-oxaspiro[3.3]heptan-6-yl)methanol (0.25 g, 1.95mmol), 1.0 eq) in DCM (10 mL) at 0° C. was added DMP (1.65 g, 3.90 mmol,2 eq). The reaction mixture was stirred at rt for 1 h. The reactionmixture was then filtered through celite and the filtrate was dilutedwith NaHCO₃ solution. The mixture was extracted with DCM and the DCMlayer was washed with water, brine, dried over Na₂SO₄ and concentratedto give crude 2-oxaspiro[3.3]heptane-6-carbaldehyde (0.1 g) as acolorless oil. The crude material was used without further purification.

The borate salts in the following table were prepared by the method ofpotassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroborateusing the appropriate commercially available piperazine in step 1.

Structure Starting material

(R)-octahydro-2H-pyrido[1,2-a]pyrazine potassium(R)-trifluoro((octahydro-2H- pyrido[1,2-a]pyrazin-2-yl)methyl)borate

(R)-hexahydropyrazino[2,1-c][1,4]oxazin- 4(3H)-one potassium(R)-trifluoro((4- oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)borate

Preparation of potassium(S)-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)trifluoroborate

Step 1. tert-butyl(R)-4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate

To a solution of tert-butyl(R)-3-(hydroxymethyl)piperazine-1-carboxylate (4.00 g, 18.5 mmol) andEt₃N (5.15 mL, 37.0 mmol) in DCM (10 mL) at −20° C. was addedmethanesulfonyl chloride (3.1 g, 27.7 mmol). The reaction mixture wasstirred for 10 min and then diluted with a solution of saturated aqueousNaHCO₃. The mixture was extracted with DCM and the organic layer wasdried over MgSO₄, filtered and concentrated. Silica gel columnchromatography (eluting with 10% MeOH in DCM) provided tert-butyl(R)-4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate(3.0 g, 8.1 mmol, 44% yield) as a gummy solid. The crude product wasused in the next step without any other purification.

Step 2. tert-butyl(S)-hexahydro-5H-isothiazolo[2,3-a]pyrazine-5-carboxylate 1,1-dioxide

To a solution of tert-butyl(R)-4-(methylsulfonyl)-3-(((methylsulfonyl)oxy)methyl)piperazine-1-carboxylate(3.0 g, 8.1 mmol) in THF (10 mL) at −78° C. was added a solution ofLHMDS (1.0 M in THF, 24.3 mL, 24.3 mmol). The reaction mixture wasstirred at −78° C. for 3 h and then diluted with a solution of saturatedaqueous NaHCO₃. The mixture was extracted with DCM and the organic layerwas dried over MgSO₄, filtered and concentrated. Silica gel columnchromatography (eluting with 50% EtOAc in hexane) provided tert-butyl(S)-hexahydro-5H-isothiazolo[2,3-a]pyrazine-5-carboxylate 1,1-dioxide(2.5 g) as a white solid. ¹H NMR (400 MHz, METHANOL-d4) δ ppm 4.35-4.12(m, 2H) 3.39-3.37 (m, 1H) 3.28-3.10 (m, 3H) 2.80-2.40 (m, 3H) 2.39-2.36(m, 1H) 2.03-1.94 (m, 1H) 1.59 (s, 9H).

Step 3: (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxidehydrochloride

A solution of HCl (4.0 M in dioxane, 3 mL) was added to a solution oftert-butyl (S)-hexahydro-5H-isothiazolo[2,3-a]pyrazine-5-carboxylate1,1-dioxide (2.5 g, 9.0 mmol) and the mixture was stirred for 2 h at rt.The reaction was then concentrated to give crude(S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxide hydrochloridewhich was used without further purification.

Step 4. potassium(S)-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)trifluoroborate

To a solution of (S)-hexahydro-2H-isothiazolo[2,3-a]pyrazine 1,1-dioxidehydrochloride (1.7 g, 8.0 mmol) in THF (20 mL) was added NaH (0.461 g,19.3 mmol), potassium (bromomethyl)trifluoroborate (1.9 g, 9.6 mmol) andtetrabutylammonium iodide (0.178 g, 0.482 mmol). The reaction mixturewas stirred at rt for 16 h. The reaction mixture was then concentratedto give potassium(S)-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)trifluoroborate(3 g, crude) as a white solid.

Preparation of tert-butyl(2S)-4-(bromomethyl)-4-fluoro-2-methylpiperidine-1-carboxylate

To a solution of tert-butyl(S)-2-methyl-4-methylenepiperidine-1-carboxylate [see Example 71](400mg, 1.89 mmol)) in DCM (10 mL) at 0° C. was added triethylaminetrihydrofluoride (0.77 mL, 4.73 mmol). The reaction mixture was stirredat 0° C. for 30 min and then NBS (500 mg, 2.83 mmol) was added. Themixture was stirred at rt for 2 h. The reaction mixture was thenbasified with saturated aqueous NaHCO₃ solution and extracted withEtOAc. The organic layer was dried over sodium sulfate, filtered andconcentrated. The crude product was purified by silica gelchromatography (eluted with 10% EtOAc/hexane) to give tert-butyl(2S)-4-(bromomethyl)-4-fluoro-2-methylpiperidine-1-carboxylate (0.35 g,60% yield) as a mixture of diastereomers that was used without furtherpurification.

Preparation of(cis)-4-(bromomethyl)-1-isobutyl-2-(trifluoromethyl)piperidine

Step 1. (cis)-methyl1-isobutyl-2-(trifluoromethyl)piperidine-4-carboxylate

Isobutyraldehyde (0.767 g, 10.7 mmol) and triethylamine (3.07 mL, 21.3mmol) were added to a solution of (cis)-methyl2-(trifluoromethyl)piperidine-4-carboxylate [see WO2021/158948, 2021,A1] (1.5 g, 7.1 mmol) in DCM (15 mL). The reaction mixture was stirredat rt for 30 min and then sodium triacetoxyborohydride (4.51 g, 21.3mmol) was added. The reaction mixture was stirred at rt for 4 h and thenquenched with a solution of saturated aqueous NaHCO₃ and extracted threetimes with DCM. The combined organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated to give crude (cis)-methyl1-isobutyl-2-(trifluoromethyl)piperidine-4-carboxylate (1.0 g) which wasused without further purification.

Step 2. (cis)-(1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methanol

A solution of LAH (2M in THF, 1.02 mL, 2.05 mmol) was added to asolution of (cis)-methyl1-isobutyl-2-(trifluoromethyl)piperidine-4-carboxylate (0.5 g, 1.87mmol) in THF (5 mL) at 0° C. The mixture was stirred at 0° C. for 2 hand then quenched with EtOAc. The mixture was washed with a solution ofsaturated aqueous ammonium chloride and the organic layer was dried overNa₂SO₄, filtered and concentrated to give crude(cis)-(1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methanol (150 mg)which was used without further purification.

Step 3. (cis)-4-(bromomethyl)-1-isobutyl-2-(trifluoromethyl)piperidine

Triphenylphosphine (427 mg, 1.62 mmol) and carbon tetrabromide (537 mg,1.62 mmol) were added in portions to a solution of(cis)-(1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methanol (130 mg,0.54 mmol) in DCM (4 mL) at 0° C. The reaction mixture was stirred at rtfor 2 h. After completion of the reaction, the mixture was diluted withDCM and washed with water. The organic layer was washed with brine,dried over Na₂SO₄, filtered and concentrated. The crude material waspurified by silica gel chromotography (eluted with 0-50% EtOAc inhexanes) to afford(cis)-4-(bromomethyl)-1-isobutyl-2-(trifluoromethyl)piperidine (60 mg,0.20 mmol, 37% yield).

Preparation of Example Compounds Example 1. Preparation of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 1)

Step 1:1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

A mixture of 3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(400 mg, 1.51 mmol), 5-bromo-3-iodopyrazolo[1,5-a]pyridine, (499 mg,1.54 mmol), cesium carbonate (986 mg, 3.03 mmol) and CuI (57.7 mg, 0.303mmol) in 1,4-dioxane (12 mL) in a microwave vial was purged withnitrogen. (±)-trans-1,2-Diaminocyclohexane (0.036 mL, 0.30 mmol) wasadded and the mixture was purged again with nitrogen. The vial wascapped and heated at 80° C. overnight in a heating block. The reactionmixture was diluted with ethyl acetate and washed with water and brine.The organic layer was dried over Na₂SO₄, filtered and concentrated.Silica gel column chromatography (eluting with 0-100% EtOAc in heptane)provided1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-das a light yellow, foamy solid. LCMS [M+H]⁺: 459.2. ¹H NMR (500 MHz,CDCl₃) δ 8.23 (dd, J=7.3, 0.8 Hz, 1H), 7.90 (s, 1H), 7.49 (dd, J=2.1,0.8 Hz, 1H), 7.14 (d, J=8.9 Hz, 1H), 6.86 (dd, J=7.3, 2.1 Hz, 1H),6.49-6.39 (m, 2H), 5.03 (s, 2H), 3.83 (s, 3H), 3.80 (m, 5H), 2.96 (t,J=6.6 Hz, 2H).

Step 2: tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate

a) A microwave vial containing tert-butyl4-methylenepiperidine-1-carboxylate (500 mg, 2.53 mmol) was purged withnitrogen for 15 min and then a solution of 9-BBN (0.5M in THF, 5.07 mL,2.53 mmol) was added. The vial was capped and the mixture was heated at80° C. for 3.5 h and then cooled to rt.

b) The reaction mixture from part a was added by syringe to a microwavevial containing a mixture of1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione,(1048 mg, 2.281 mmol), K₂CO₃ (438 mg, 3.17 mmol) and PdCl₂(dppf).CH₂Cl₂adduct (54 mg, 0.066 mmol) in DMF (14 mL) and water (1.4 mL). The vialwas capped and the reaction mixture was heated overnight at 60° C. Thereaction mixture was then cooled to rt and diluted with ethyl acetateand washed sequentially with water and brine. The organic layer wasdried over sodium sulfate, filtered and concentrated. Silica gel columnchromatography (eluted with 0-100% EtOAc in heptane) provided tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylateas a light yellow, foamy solid. LCMS [M+H]⁺: 578.4.

Step 3:3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride

A solution of HCl (4.0 M in dioxane, 15 ml, 60 mmol) was added totert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate(1270 mg, 2.154 mmol) and the mixture was stirred for 2 h at rt. Thereaction was then concentrated to give crude3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride. LCMS [M+H]⁺: 478.4.

Step 4:1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

To a solution of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (100 mg, 0.195 mmol) in DMF (3 mL) was added potassiumcarbonate (81 mg, 0.58 mmol) and (bromomethyl)cyclohexane (0.081 mL,0.58 mmol). The mixture was heated at 80° C. for 4 h and then cooled tort. The mixture was diluted with ethyl acetate and washed sequentiallywith water and brine. The organic layer was dried over sodium sulfate,filtered and concentrated to give crude1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 574.4.

Step 5:1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (2 mL, 26 mmol) was added to crude1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(30 mg, 0.0525 mmol) and the mixture was heated at 80° C. overnight. Themixture was then cooled to rt, concentrated and the residue wasdissolved in toluene and concentrated again. The residue was dissolvedin DMSO, filtered through a 1 micron filter and purified by reversephase HPLC using ACN/Water/0.1% formic acid. The fractions containingthe product were combined, frozen and lyophilized to afford a formatesalt of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 424.3. ¹H NMR (500 MHz, DMSO-d6) δ 10.44 ((, 1H), 8.58 (d,J=7.1 Hz, 1H), 8.16 (5, 1H), 8.00 (s, 1H), 7.37 (d, J=1.8 Hz, 1H), 6.79(dd, J=7.2, 1.9 Hz, 1H), 3.77 (t, J=6.7 Hz, 2H), 3.59-3.26 (m, 2H), 3.19(d, J=12.2 Hz, 3H), 2.79 (t, J=6.7 Hz, 2H), 2.60 (d, J=6.8 Hz, 2H), 2.56(s, 1H), 1.82-1.58 (m, 9H), 1.41 (q, J=12.4 Hz, 2H), 1.30-1.09 (m, 3H),0.96-0.82 (n, 2H).

The compounds in the following table were prepared by the method ofExample 1, using the appropriate commercially available halide,mesylate, tosylate or triflate in step 4.

Example Mass No. Structure [M + H] ¹H NMR 2 

410.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 4.6 Hz, 1H), 8.60 (d, J = 7.1Hz, 1H), 8.01 (s, 1H), 7.45- 7.26 (m, 1H), 6.80 (dd, J = 7.1, 1.9 Hz,1H), 3.78 (td, J = 6.7, 2.8 Hz, 2H), 3.57-3.39 (m, 2H), 3.30- 3.12 (m,1H), 3.02 (dd, J = 7.2, 5.4 Hz, 2H), 2.87 (dt, J = 14.1, 10.6 Hz, 2H),2.79 (t, J = 6.7 1-(5-((1-(cyclopentylmethyl)piperidin-4- Hz, 2H), 2.62(d, J = 6.6 yl)methyl)pyrazolo[1,5-a]pyridin-3- Hz, 2H), 2.20 (h, J =7.4 yl)dihydropyrimidine-2,4(1H,3H)-dione Hz, 1H), 1.94-1.70 (m, 4H),1.62 (tdq, J = 9.7, 6.8, 3.8, 3.1 Hz, 2H),1.58-1.41 (m, 4H), 1.31-1.11(m, 2H). 3 

426.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 5.4 Hz, 1H), 8.60 (dd, J = 7.2,2.6 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.42- 7.35 (m, 1H), 6.80 (dt, J =7.2, 2.1 Hz, 1H), 3.85 (ddd, J = 11.6, 4.5, 1.9 Hz, 2H), 3.78 (td, J =6.7, 3.5 Hz, 2H), 3.55- 3.45 (m, 2H), 3.31 (td, J = 11.7, 2.1 Hz, 2H),2.94 1-(5-((1-((tetrahydro-2H-pyran-4- (t, J = 6.2 Hz, 2H), 2.87yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5- (dt, J = 13.9, 10.9 Hz,a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- 2H), 2.79 (t, J = 6.7 Hz,dione 2H), 2.62 (d, J = 6.6 Hz, 2H), 2.04 (ddt, J = 11.2, 7.3, 3.9 Hz,1H), 1.92- 1.71 (m, 3H), 1.69-1.58 (m, 2H), 1.56-1.42 (m, 2H), 1.22 (qd,J = 12.0, 4.5 Hz, 2H). 4 

460.4 (500 MHz, DMSO-d6) δ 10.36 (d, J = 5.1 Hz, 1H), 8.52 (d, J = 7.3Hz, 1H), 7.93 (s, 1H), 7.29 (d, J = 15.4 Hz, 1H), 6.72 (d, J = 7.1 Hz,1H), 3.69 (t, J = 6.8 Hz, 2H), 3.14 (s, 1H), 2.88 (t, J = 6.3 Hz, 2H),2.79 (dd, J = 20.7, 8.9 Hz, 2H), 2.71 (t, J = 6.7 Hz, 2H), 2.54 (d, J =6.5 Hz, 2H), 2.02- 1-(5-((1-((4,4- 1.90 (m, 3H), 1.83-difluorocyclohexyl)methyl)piperidin-4- 1.63 (m, 8H), 1.43 (q, J =yl)methyl)pyrazolo[1,5-a]pyridin-3- 12.4, 11.6 Hz, 2H),yl)dihydropyrimidine-2,4(1H,3H)-dione 1.15 (q, J = 13.1 Hz, 2H). 5 

382.2 (500 MHz, DMSO-d6) δ 10.45 (d, J = 5.4 Hz, 1H), 8.60 (dd, J = 7.1,3.0 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 6.80(dd, J = 7.2, 1.9 Hz, 1H), 5.77 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H),5.31-5.08 (m, 2H), 3.78 (td, J = 6.7, 3.3 Hz, 2H), 3.58- 3.38 (m, 2H),3.25 (d, J = 1-(5-((1-(cyclopropylmethyl)piperidin-4- 6.3 Hz, 1H), 3.15-yl)methyl)pyrazolo[1,5-a]pyridin-3- 3.03 (m, 2H), 2.96-2.83yl)dihydropyrimidine-2,4(1H,3H)-dione (m, 2H), 2.79 (t, J = 6.8 Hz, 2H),2.61 (d, J = 6.5 Hz, 2H), 2.43 (dtd, J = 9.7, 6.4, 1.6 Hz, 2H), 1.83 (d,J = 13.8 Hz, 2H), 1.43 (q, J = 13.1 Hz, 2H). 6 

438.4 (500 MHz, DMSO-d6) δ 10.45 (d, J = 5.6 Hz, 1H), 8.68-8.49 (m, 1H),8.01 (d, J = 2.5 Hz, 1H), 7.46-7.24 (m, 1H), 6.80 (dd, J = 7.1, 1.9 Hz,1H), 3.78 (t, J = 6.7 Hz, 2H), 3.53-3.41 (m, 2H), 3.28- 3.10 (m, 1H),3.03 (dt, J = 11.2, 5.3 Hz, 2H), 2.90-2.72 (m, 4H), 2.61 (d, J = 6.6 Hz,2H), 1.83 (t, J = 15.3 Hz, 2H), 1.77- 1.57 (m, 5H), 1.57- 1.47 (m, 2H),1.41 (q, J = 1-(5-((1-(2-cyclohexylethyl)piperidin-4- 13.1 Hz, 2H), 1.18yl)methyl)pyrazolo[1,5-a]pyridin-3- (ddd, J = 26.1, 22.5, 12.0yl)dihydropyrimidine-2,4(1H,3H)-dione Hz, 4H), 0.92 (q, J = 11.9 Hz,2H). 7 

426.3 1H NMR (500 MHz, DMSO-d6) δ 10.36 (d, J = 4.0 Hz, 1H), 8.52 (d, J= 7.2 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.30 (s, 1H), 6.71 (dd, J =7.2, 1.9 Hz, 1H), 3.75-3.67 (m, 4H), 3.62 (dt, J = 11.5, 4.2 Hz, 2H),3.44 (s, 2H), 3.19-3.02 (m, 1H), 2.92-2.74 (m, 3H), 2.71 (t, J = 6.7 Hz,2H), 1-(5-((1-((tetrahydro-2H-pyran-3- 2.58-2.51 (m, 2H),yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5- 1.92 (s, 1H), 1.72 (d, J =a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- 14.5 Hz, 3H), 1.59- dione1.47 (m, 1H), 1.41 (dt, J = 13.5, 9.7 Hz, 3H), 1.31- 1.14 (m, 1H). 8 

438.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 4.7 Hz, 1H), 8.60 (dt, J = 7.2,1.3 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.46- 7.28 (m, 1H), 6.80 (dd, J =7.2, 1.8 Hz, 1H), 3.78 (td, J = 6.7, 2.8 Hz, 2H), 3.47 (d, J = 12.2 Hz,2H), 3.21 (s, 1H), 2.92-2.83 (m, 3H), 2.79 (td, J = 6.7, 1.8 Hz, 2H),2.62 1-(5-((1-(cycloheptylmethyl)piperidin-4- (d, J = 6.6 Hz, 2H), 2.00-yl)methyl)pyrazolo[1,5-a]pyridin-3- 1.66 (m, 6H), 1.65-yl)dihydropyrimidine-2,4(1H,3H)-dione 1.38 (m, 10H), 1.27- 1.09 (m, 2H).9 

398.3 (500 MHz, DMSO-d6) δ 10.44 (d, J = 4.6 Hz, 1H), 8.60 (s, 1H), 8.01(s, 1H), 7.37 (d, J = 11.6 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 3.77 (t, J= 6.8 Hz, 2H), 3.46 (s, 2H), 3.21(s, 1H), 3.00- 2.81 (m, 3H), 2.79 (t, J= 6.6 Hz, 2H), 2.62 (d, J = 6.5 Hz, 2H), 1.92- 1.71 (m, 4H), 1.65-1.33(m, 3H), 1.16 (dq, J = 14.3, 7.2 Hz, 1H), 0.91 (dp, J =1-(5-((1-(2-methylbutyl)piperidin-4- 23.0, 7.3, 6.9 Hz, 6H).yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 10

452.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 8.01(s, 1H), 7.36 (d, J = 11.5 Hz, 1H), 6.79 (d, J = 7.3 Hz, 1H), 3.77 (t, J= 6.6 Hz, 2H), 3.51 (d, J = 12.2 Hz, 4H), 3.21 (s, 1H), 3.01 (q, J =6.3, 5.6 Hz, 1H), 2.97-2.70 (m, 4H), 2.62 (d, J = 6.5 Hz, 1H), 1.93-1.68(m, 5H), 1.67- 1.39 (m, 5H), 1.33- 0.92 (m, 6H), 0.89 (d, J = 6.8 Hz,3H). 1-(5-((1-(2-cyclohexylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 11

440.2 (500 MHz, DMSO-d6) δ 10.44 (d, J = 5.6 Hz, 1H), 8.59 (d, J = 7.2Hz, 1H), 8.00 (s, 1H), 7.37 (d, J = 13.5 Hz, 1H), 6.79 (d, J = 7.2 Hz,1H), 3.88-3.79 (m, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.27 (q, J = 11.8 Hz,4H), 3.04 (dt, J = 11.1, 5.4 Hz, 2H), 2.93-2.70 (m, 4H), 2.61 (d, J =6.5 Hz, 2H), 1.83 (t, J = 14.6 Hz, 3H), 1.56 (d, J = 13.4 Hz, 5H), 1.40(q, J = 13.0 1-(5-((1-(2-(tetrahydro-2H-pyran-4- Hz, 2H), 1.17 (qd, J =yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5- 12.2, 4.5 Hz, 2H).a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione 12

426.3 (400 MHz, DMSO) δ 10.41 (s, 1H), 8.65 (s, 1H), 8.58 (d, J = 7.1Hz, 1H), 7.99 (s, 1H), 7.36 (d, J = 1.8 Hz, 1H), 6.77 (dd, J = 7.2, 1.9Hz, 1H), 3.76 (t, J = 6.7 Hz, 2H), 3.31 (d, J = 12.0 Hz, 2H), 3.05 (s,1H), 3.02- 2.92 (m, 2H), 2.78 (t, J = 6.7 Hz, 2H), 2.60 (d, J = 6.7 Hz,2H), 1.92 (s, 1H), 1.84-1.61 (m, 4H), 1.56-1.39 (m, 4H), 1.34 (ddq, J =13.6, 9.8, 7.0 Hz, 4H), 0.90 (t, J = 7.2 Hz, 6H).1-(5-((1-(heptan-4-yl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 13

410.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 8.00(s, 1H), 7.37 (d, J = 11.6 Hz, 1H), 6.79 (d, J = 7.1 Hz, 1H), 3.77 (t, J= 6.7 Hz, 2H), 3.21 (s, 1H), 3.00 (d, J = 8.3 Hz, 1H), 2.94- 2.71 (m,6H), 2.60 (d, J = 6.5 Hz, 2H), 2.23 (dq, J = 15.5, 7.7 Hz, 1H), 2.13-1.97 (m, 2H), 1.83 (dd, J = 17.2, 10.7 Hz, 5H), 1.72 (dd, J = 10.5, 6.21-(5-((1-(2-cyclobutylethyl)piperidin-4 Hz, 2H), 1.63 (h, J = 9.4yl)methyl)pyrazolo[1,5-a]pyridin-3- Hz, 2H), 1.40 (q, J =yl)dihydropyrimidine-2,4(1H,3H)-dione 13.1, 12.7 Hz, 2H). 14

412.3 (500 MHz, Methanol-d4) δ 8.34 (dd, J = 7.2, 0.9 Hz, 1H), 7.91 (s,1H), 7.27 (dd, J = 2.0, 1.0 Hz, 1H), 6.73 (dd, J = 7.2, 1.9 Hz, 1H),3.84 (dd, J = 8.8, 7.1 Hz, 1H), 3.81- 3.74 (m, 3H), 3.66 (dt, J = 8.5,7.5 Hz, 1H), 3.51 (t, J = 15.4 Hz, 2H), 3.37 (dd, J = 8.8, 6.5 Hz, 1H),3.11-3.03 (m, 2H), 2.85 1-(5-((1-((tetrahydrofuran-3- (t, J = 12.8 Hz,2H), 2.79 yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5- (t, J = 6.8 Hz,2H), 2.60 a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- (dd, J = 6.8, 3.7Hz, 3H), dione 2.10 (dtd, J = 12.6, 7.8, 4.8 Hz, 1H), 1.89 (dd, J =29.1, 13.1 Hz, 3H), 1.58 (dq, J = 12.5, 7.6 Hz, 1H), 1.46 (q, J = 13.4Hz, 2H). 15

412.2 (400 MHz, Methanol-d4) δ 8.43 (d, J = 7.2 Hz, 1H), 8.35 (s, 1H),8.00 (s, 1H), 7.36 (s, 1H), 6.82 (d, J = 7.1 Hz, 1H), 4.25 (ddt, J =10.0, 7.1, 3.7 Hz, 1H), 3.96-3.84 (m, 3H), 3.81 (q, J = 7.4 Hz, 1H),3.61 (d, J = 12.4 Hz, 2H), 3.37- 3.14 (m, 2H), 3.08 (dd, J = 13.3, 10.4Hz, 1H), 1-(5-((1-((tetrahydrofuran-2- 3.04-2.92 (m, 2H),yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5- 2.88 (t, J = 6.8 Hz, 2H),a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- 2.70 (d, J = 7.0 Hz, 2H),dione 2.21-2.07 (m, 1H), 2.06-1.85 (m, 5H), 1.68-1.48 (m, 3H). NHprotons were not observed due to solvent exchange 16

424.3 (500 MHz, DMSO-d6) δ 10.44 (d, J = 5.9 Hz, 1H), 8.59 (d, J = 7.2Hz, 1H), 8.00 (s, 1H), J = 10.9 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H), 3.77(t, J = 6.7 Hz, 2H), 3.22 (s, 1H), 2.99 (dt, J = 10.5, 5.0 Hz, 2H), 2.86(t, J = 11.7 Hz, 2H), 2.82- 2.72 (m, 3H), 2.60 (d, J = 6.6 Hz, 2H),1.90- 1.68 (m, 6H), 1.68- 1.55 (m, 4H), 1.54-1.36 (m,1-(5-((1-(2-cyclopentylethyl)piperidin-4- 4H), 1.10 (d, J = 7.4 Hz,yl)methyl)pyrazolo[1,5-a]pyridin-3- 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 17

4193 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.69 (dd, J = 5.1, 1.7 Hz, 2H),8.59 (d, J = 7.1 Hz, 1H), 8.01 (s, 1H), 7.96 (dt, J = 7.9, 2.0 Hz, 1H),7.56 (dd, J = 7.9, 4.9 Hz, 1H), 7.37 (s, 1H), 6.79 (dd, J = 7.1, 1.9 Hz,1H), 4.35 (d, J = 4.0 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.39 (d, J =12.0 1-(5-((1-(pyridin-3-ylmethyl)piperidin-4- Hz, 2H), 2.94 (q, J =yl)methyl)pyrazolo[1,5-a]pyridin-3- 11.5 Hz, 2H), 2.79 (t, J =yl)dihydropyrimidine-2,4(1H,3H)-dione 6.7 Hz, 2H), 2.60 (d, J = 6.5 Hz,2H), 2.00-1.69 (m, 3H), 1.51-1.23 (m, 2H). 18

396.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 6.0 Hz, 1H), 8.63-8.55 (m, 1H),8.01 (d, J = 2.6 Hz, 1H), 7.38 (d, J = 1.8 Hz, 1H), 6.79 (dd, J = 7.2,1.9 Hz, 1H), 3.77 (t, J = 6.7 Hz, 2H), 3.35 (d, J = 12.0 Hz, 2H),3.26-3.13 (m, 1H), 3.08 (dd, J = 7.1, 5.1 Hz, 2H), 2.86 (t, J = 11.8 Hz,3H), 2.75- 1-(5-((1-(cyclobutylmethyl)piperidin-4- 2.64 (m, 1H), 2.60(d, J = yl)methyl)pyrazolo[1,5-a]pyridin-3- 6.6 Hz, 2H), 2.07 (dtd, J =yl)dihydropyrimidine-2,4(1H,3H)-dione 10.6, 6.8, 3.7 Hz, 2H), 1.98-1.69(m, 7H), 1.41 (q, J = 13.1 Hz, 2H). 19

398.4 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 8.00(d, J = 2.8 Hz, 1H), 7.37 (d, J = 11.8 Hz, 1H), 6.79 (d, J = 7.1 Hz,1H), 3.76 (dt, J = 7.0, 4.0 Hz, 2H), 3.27-3.10 (m, 2H), 3.01 (qd, J =8.4, 5.1, 3.7 Hz, 2H), 2.93-2.67 (m, 4H), 2.68-2.55 (m, 2H), 1.80 (p, J= 20.8, 19.2 Hz, 3H), 1.59 (dt, J = 14.0, 7.9 Hz, 1H), 1.521-(5-((1-isopentylpiperidin-4- (t, J = 8.1 Hz, 2H), 1.40yl)methyl)pyrazolo[1,5-a]pyridin-3- (q, J = 13.5 Hz, 2H),yl)dihydropyrimidine-2,4(1H,3H)-dione 0.89 (d, J = 6.5 Hz, 6H). 20

398.4 (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 8.00(d, J = 1.7 Hz, 1H), 7.37 (s, 1H), 6.78 (dd, J = 7.1, 1.9 Hz, 1H), 3.77(t, J = 6.8 Hz, 2H), 3.34 (d, J = 12.0 Hz, 2H), 2.98 (d, J = 11.5 Hz,3H), 2.78 (td, J = 6.9, 1.9 Hz, 2H), 2.61 (d, J = 6.7 Hz, 2H), 2.00-1.70(m, 5H), 1.66- 1.33 (m, 4H), 0.95 (td, J = 7.4, 1.8 Hz, 6H).1-(5-((1-(pentan-3-yl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 21

433.4 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.78- 8.65 (m, 2H), 8.58 (d, J= 7.1 Hz, 1H), 8.15- 7.94 (m, 2H), 7.71-7.55 (m, 1H), 7.35 (d, J = 1.6Hz, 1H), 6.76 (dd, J = 7.2, 1.8 Hz, 1H), 4.62 (d, J = 7.9Hz, 2H), 3.76(t, J = 6.7 Hz, 2H), 3.61 (d, J = 11.9 Hz, 1H), 3.30 (d, J = 12.1 Hz,1H), 2.77 (q, J = 11.3, 9.0 Hz, 4H), 2.591-(5-((1-(1-(pyridin-3-yl)ethyl)piperidin-4- (d, J = 6.3 Hz, 1H), 1.81yl)methyl)pyrazolo[1,5-a]pyridin-3- (dd, J = 31.0, 11.2 Hz,yl)dihydropyrimidine-2,4(1H,3H)-dione 3H), 1.67 (d, J = 6.9 Hz, 3H),1.45 (dt, J = 28.2, 13.6 Hz, 2H). 22

436.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 14.1 Hz, 8.60 (dd, J = 10.0,7.1 Hz, 1H), 8.01 (s, 1H), 7.54 (td, J = 8.0, 6.1 Hz, 1H), 7.49-7.26 (m,4H), 6.79 (td, J = 7.2, 6.3, 1.9 Hz, 1H), 4.30 (d, J = 5.0 Hz, 2H), 3.77(t, J = 6.7 Hz, 2H), 3.36 (d, J = 12.0 Hz, 2H), 2.91 (q, J = 11.6 Hz,2H), 2.79 (t, J = 1-(5-((1-(3-fluorobenzyl)piperidin-4- 6.7 Hz, 2H),2.60 (d, J = yl)methyl)pyrazolo[1,5-a]pyridin-3- 6.5 Hz, 2H), 1.95-yl)dihydropyrimidine-2,4(1H,3H)-dione 1.70 (m, 3H), 1.42 (q, J = 13.0Hz, 2H). 23

436.3 (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.57 (d, J = 7.2 Hz, 1H), 7.99(s, 1H), 7.52 (dd, J = 8.6, 5.4 Hz, 2H), 7.37-7.28 (m, 3H), 6.77 (dd, J= 7.2, 1.9 Hz, 1H), 4.25 (d, J = 5.0 Hz, 2H), 3.75 (q, J = 6.4 Hz, 2H),3.33 (d, J = 12.1 Hz, 2H), 2.87 (d, J = 12.0 Hz, 2H), 2.77 (t, J = 6.7Hz, 1-(5-((1-(4-fluorobenzyl)piperidin-4- 2H), 2.58 (m, 3H), 1.83-yl)methyl)pyrazolo[1,5-a]pyridin-3- 1.73 (m, 2H), 1.44-yl)dihydropyrimidine-2,4(1H,3H)-dione 1.35 (m, 2H). 24

356.3 (400 MHz, DMSO-d6) δ 10.42 (d, J = 4.5 Hz, 1H), 8.59 (dt, J = 7.1,1.3 Hz, 1H), 8.00 (s, 1H), 7.45-7.31 (m, 1H), 6.79 (dd, J = 7.2, 1.9 Hz,1H), 3.77 (t, J = 6.7 Hz, 2H), 3.45 (d, J = 12.2 Hz, 2H), 3.29-3.14 (m,1H), 3.12-3.00 (m, 2H), 2.94-2.71 (m, 4H), 2.61 (d, J = 6.5 Hz, 2H),1-(5-((1-ethylpiperidin-4- 1.82 (d, J = 13.5 Hz, 2H),yl)methyl)pyrazolo[1,5-a]pyridin-3- 1.40 (q, J = 13.0 Hz,yl)dihydropyrimidine-2,4(1H,3H)-dione 2H), 1.19 (t, J = 7.3 Hz, 3H). 25

486.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.01(s, 1H), 7.91 (s, 1H), 7.86 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 7.7 Hz,1H), 7.73 (q, J = 7.7, 7.0 Hz, 1H), 7.37 (d, J = 1.8 Hz, 1H), 6.84-6.75(m, 1H), 4.39 (d, J = 4.8 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.37 (d, J= 12.0 Hz, 1-(5-((1-(3-(trifluoromethyl)benzyl)piperidin- 2H), 2.94 (q,J = 11.5 Hz, 4-yl)methyl)pyrazolo[1,5-a]pyridin-3- 2H), 2.78 (t, J = 6.7Hz, yl)dihydropyrimidine-2,4(1H,3H)-dione 2H), 2.61 (d, J = 6.5 Hz, 2H),2.02-1.66 (m, 3H), 1.42 (q, J = 13.1 Hz, 2H). 26

432.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8.00(s, 1H), 7.61-7.42 (m, 5H), 7.35 (s, 1H), 6.91-6.55 (m, 1H), 4.48 (dt, J= 11.9, 5.9 Hz, 1H), 3.76 (t, J = 6.7 Hz, 2H), 3.64 (d, J = 12.0 Hz,1H), 3.29-3.10 (m, 1H), 2.87- 2.63 (m, 4H), 2.59 (d, J = 6.3 Hz, 2H),1.95- 1.71 (m, 3H), 1.64 (d, J = 6.9 Hz, 3H), 1.44 (dq, J =1-(5-((1-(1-phenylethyl)piperidin-4- 41.1, 12.9, 12.2 Hz,yl)methyl)pyrazolo[1,5-a]pyridin-3- 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 27

502.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.01(s, 1H), 7.70-7.58 (m,1H), 7.60-7.47 (m, 3H), 7.37 (s, 1H), 6.92-6.64(m, 1H), 4.34 (d, J = 4.9 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.36 (d, J= 12.0 Hz, 2H), 2.92 (q, J = 11.6 Hz, 2H), 2.79 (t, J = 6.7 Hz, 2H),2.60 (d, J = 1-(5-((1-(3- 6.5 Hz, 2H), 1.79 (dd, J =(trifluoromethoxy)benzyl)piperidin-4- 34.7, 12.8 Hz, 3H), 1.42yl)methyl)pyrazolo[1,5-a]pyridin-3- (q, J = 13.1 Hz, 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 28

419.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.71 (s, 2H), 8.58 (d, J = 7.2Hz, 1H), 8.00 (s, 1H), 7.51 (d, J = 5.1 Hz, 2H), 7.36 (s, 1H), 6.78 (dd,J = 7.1, 1.9 Hz, 1H), 4.32 (d, J = 4.7 Hz, 2H), 3.76 (t, J = 6.7 Hz,2H), 3.37 (d, J = 11.9 Hz, 2H), 2.94 (d, J = 12.0 Hz, 2H), 2.78 (t, J =6.7 Hz, 1-(5-((1-(pyridin-4-ylmethyl)piperidin-4- 2H), 2.60 (d, J = 6.5yl)methyl)pyrazolo[1,5-a]pyridin-3- Hz, 2H), 1.82 (d, J = 14.8yl)dihydropyrimidine-2,4(1H,3H)-dione Hz, 3H), 1.41 (q, J = 13.1 Hz,2H). 29

418.3 (400 MHz, DMSO-d6) δ 10.42 (d, J = 12.8 Hz, 1H), 8.63-8.52 (m,1H), 8.00 (d, J = 6.5 Hz,1H), 7.47 (s, 5H), 7.41-7.32 (m, 1H), 6.85-6.74(m, 1H), 4.26 (d, J = 5.0 Hz, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.35 (d, J= 12.1 Hz, 2H), 2.90 (q, J = 11.7 Hz, 2H), 2.78 (t, J = 6.7 Hz, 2H),2.59 (d, J = 1-(5-((1-benzylpiperidin-4- 6.4 Hz, 2H), 1.78 (dd, J =yl)methyl)pyrazolo[1,5-a]pyridin-3- 25.2, 11.7 Hz, 3H),yl)dihydropyrimidine-2,4(1H,3H)-dione 1.41 (q, J = 13.1 Hz, 2H). 30

410.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.57 (dd, J = 7.1, 0.9 Hz,1H), 8.00 (s, 1H), 7.36 (dd, J = 1.9, 0.9 Hz, 1H), 6.79 (dd, J = 7.2,1.9 Hz, 1H), 4.18 (d, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.11 (d, J = 62.3Hz, 3H), 2.79 (t, J = 6.7 Hz, 2H), 2.59 (d, J = 6.7 Hz, 3H), 2.56 (s,1H), 1.67 (d, J = 13.8 1-(5-((1-(2,2,2-trifluoroethyl)piperidin-4- Hz,3H), 1.36 (d, J = yl)methyl)pyrazolo[1,5-a]pyridin-3- 13.1 Hz, 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 31

442.2 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.56 (d, J = 7.4 Hz, 1H), 7.99(s, 1H), 7.36 (s, 1H), 6.78 (dd, J = 7.1, 1.9 Hz, 1H), 6.50 (t, J = 52.4Hz, 1H), 3.77 (t, J = 6.7 Hz, 2H), 3.59 (s, 4H), 2.93 (s, 2H), 2.79 (t,J = 6.7 Hz, 2H), 2.57 (d, J = 9.4 Hz, 2H), 2.45-2.05 (m, 1H), 1.61 (s,3H), 1.37 (d, J = 56.0 Hz, 2H).1-(5-((1-(2,2,3,3-tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 32

432.1 As formate salt-(400 MHz, CD₃OD) δ 8.44 (brs, 1H), 8.42 (d, J =6.8 Hz, 1H), 7.99 (s, 1H), 7.36 (s, 1H), 6.82 (d, J = 7.2 Hz, 1H), 3.87(t, J = 6.8 Hz, 2H), 3.45- 3.42 (m, 2H), 3.20-3.19 (m, 2H), 2.89-2.40(m, 11H), 1.92-1.88 (m, 3H), 1.55-1.53 (m, 2H) ppm. NH protons not1-(5-((1-((3,3- observed due to solventdifluorocyclobutyl)methyl)piperidin-4- exchangeyl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 33

437.4 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.71 (d, J = 2.8 Hz, 1H),8.68- 8.50 (m, 2H), 8.01 (s, 1H), 7.89 (ddd, J = 9.6, 2.8, 1.7 Hz, 1H),7.37 (d, J = 1.8 Hz, 1H), 6.79 (dd, J = 7.1, 1.9 Hz, 1H), 4.38 (d, J =3.3 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.41 (d, J = 12.0 Hz, 2H), 3.01-1-(5-((1-((5-fluoropyridin-3- 2.87 (m, 2H), 2.79 (t, J =yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5- 6.7 Hz, 2H), 2.61 (d, J =a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- 6.5 Hz, 2H), 1.98-1.69dione (m, 3H), 1.41 (q, J = 13.1 Hz, 2H). 34

386.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 4.9 Hz, 1H), 8.60 (dd, J = 7.1,3.2 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.42- 7.32 (m, 1H), 6.80 (dd, J =7.2, 1.9 Hz, 1H), 3.78 (td, J = 6.7, 2.8 Hz, 2H), 3.65 (dt, J = 10.0,5.0 Hz, 2H), 3.47 (d, J = 12.0 Hz, 2H), 3.32 (d, J = 11.6 Hz, 3H), 3.24(q, 1-(5-((1-(2-methoxyethyl)piperidin-4- J = 5.1 Hz, 2H), 2.91yl)methyl)pyrazolo[1,5-a]pyridin-3- (q, J = 11.7 Hz, 2H), 2.79yl)dihydropyrimidine-2,4(1H,3H)-dione (t, J = 6.7 Hz, 2H), 2.60 (d, J =6.7 Hz, 2H), 1.81 (q, J = 12.7, 8.1 Hz, 3H), 1.48 (q, J = 12.9 Hz, 2H).35

372.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 5.1 Hz, 1H), 9.10 (s, 1H), 8.60(dd, J = 7.2, 2.8 Hz, 1H), 8.01 (d, J = 2.2 Hz, 1H), 7.38 (d, J = 12.6Hz, 1H), 6.80 (dd, J = 7.1, 1.9 Hz, 1H), 3.78 (t, J = 6.7 Hz, 2H), 3.72(t, J = 5.3 Hz, 2H), 3.49 (d, J = 12.1 Hz, 2H), 3.24 (dd, J = 13.4, 7.7Hz, 1-(5-((1-(2-hydroxyethyl)piperidin-4- 1H), 3.11 (q, J = 5.3 Hz,yl)methyl)pyrazolo[1,5-a]pyridin-3- 2H), 2.90 (t, J = 11.7 Hz,yl)dihydropyrimidine-2,4(1H,3H)-dione 1H), 2.79 (td, J = 6.8, 2.2 Hz,2H), 2.60 (d, J = 6.7 Hz, 2H), 1.94-1.66 (m, 3H), 1.49 (q, J = 13.1,12.4 Hz, 2H). 36

433.2 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.55(d, J = 2.1 Hz, 1H), 8.50 (d, J = 2.0 Hz, 1H), 8.01 (s, 1H), 7.87-7.69(m, 1H), 7.43-7.25 (m, 1H), 6.79 (dd, J = 7.2, 1.9 Hz, 1H), 4.30 (d, J =3.6 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.38 (d, J = 12.0 Hz, 2H), 2.93(d, J = 1-(5-((1-((5-methylpyridin-3- 11.2 Hz, 2H), 2.79 (t, J =yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5- 6.7 Hz, 2H), 2.60 (d, J =a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- 6.5 Hz, 2H), 2.36 (s, dione3H), 1.82 (q, J = 18.9, 17.6 Hz, 3H), 1.41 (q, J = 13.1 Hz, 2H). 37

370.3 (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.60 (d, J = 7.0 Hz, 1H), 8.01(s, 1H), 7.39 (d, J = 1.8 Hz, 1H), 6.79 (dd, J = 7.3, 1.9 Hz, 1H), 3.78(t, J = 6.7 Hz, 2H), 3.34 (d, J = 12.4 Hz, 2H), 3.26- 3.18 (m, 1H), 2.92(dt, J = (t, J = 6.8 Hz, 2H), 2.62 (d, J = 6.7 Hz, 2H), 1.97- 1.78 (m,3H), 1.45 (qd, J = 13.6, 3.7 Hz, 2H), 1.22 (d, J = 6.6 Hz, 6H).1-(5-((1-isopropylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 38

436.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.01(s, 1H), 7.57 (dtd, J = 13.7, 7.5, 1.8 Hz, 2H), 7.41- 7.28 (m, 3H),6.85-6.75 (m, 1H), 4.33 (d, J = 4.8 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H),3.40 (d, J = 12.0 Hz, 2H), 2.99 (d, J = 11.8 Hz, 2H), 2.79 (q, J = 6.5Hz, 2H), 2.60 (d, J = 6.6 Hz, 2H), 1.82 (q, J = 20.3, 18.4 Hz, 3H),1-(5-((1-(2-fluorobenzyl)piperidin-4- 1.43 (d, J = 13.0 Hz,yl)methyl)pyrazolo[1,5-a]pyridin-3- 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 39

402.2 (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.59 (d, J = 7.3 Hz, 1H), 8.00(s, 1H), 7.36 (d, J = 8.6Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 3.77 (t, J =6.7 Hz, 2H), 3.54 (s, 2H), 3.39 (d, J = 25.2 Hz, 2H), 3.01 (d, J = 11.9Hz, 2H), 2.79 (t, J = 6.9 Hz, 2H), 2.65 (dd, J = 37.4, 7.6 Hz, 2H),2.00-1.69 (m, 1-(5-((1-(2-fluoro-2-methylpropyl)piperidin-4- 3H),1.69-1.52 (m, 2H), yl)methyl)pyrazolo[1,5-a]pyridin-3- 1.46 (dd, J =21.5, 10.4 yl)dihydropyrimidine-2,4(1H,3H)-dione Hz, 6H).  39a

382.1 (500 MHz, DMSO-d6) δ 10.45 (d, J = 5.0 Hz, 1H), 8.60 (dt, J = 7.2,0.9 Hz, 1H), 8.02 (d, J = 2.3 Hz, 1H), 7.43- 7.27 (m, 1H), 6.80 (dt, J =7.2, 1.8 Hz, 1H), 5.32- 5.21 (m, 1H), 5.16 (d, J = 1.7 Hz, 1H), 3.83-3.74 (m, 2H), 3.66 (d, J = 5.6 Hz, 1H), 3.52 (d, J = 12.1 Hz, 1H), 3.46-1-(5-((1-(2-methylallyl)piperidin-4- 3.33 (m, 2H), 3.21-2.96yl)methyl)pyrazolo[1,5-a]pyridin-3- (m, 1H), 2.87 (t, J = 11.9yl)dihydropyrimidine-2,4(1H,3H)-dione Hz, 1H), 2.79 (t, J = 6.7 Isolatedduring synthesis of Example 39 Hz, 2H), 2.67-2.59 (m, 2H), 1.91-1.72 (m,4H), 1.60 (td, J = 27.4, 25.3, 11.8 Hz, 1H), 1.47 (dd, J = 21.5, 12.9Hz, 3H). 40

448.4 (500 MHz, DMSO-d6) δ 10.45 (d, J = 14.0 Hz, 1H), 8.60 (dd, J =9.9, 7.1 Hz, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.56- 7.30 (m, 2H),7.19-6.96 3H), 6.80 (ddd, J = 12.4, 7.2, 1.9 Hz, 1H), 4.24 (d, J = 5.2Hz, 2H), 3.78 (d, J = 12.4 Hz, 5H), 3.35 (d, J = 12.1 Hz, 2H), 2.91 (t,J = 11.8 Hz, 2H), 2.78 (t, J = 6.6 Hz, 2H), 2.60 (d, J =1-(5-((1-(3-methoxybenzyl)piperidin-4- 6.5 Hz, 2H), 1.93-1.6yl)methyl)pyrazolo[1,5-a]pyridin-3- (m, 3H), 1.42 (q, J =yl)dihydropyrimidine-2,4(1H,3H)-dione 13.1 Hz, 2H). 41

432.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 16.5 Hz, 1H), 8.60 (dd, J =11.1, 7.1 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.48 (dd, J = 15.1, 7.7 Hz,1H), 7.43- 7.21 (m, 4H), 6.87- 6.73 (m, 1H), 4.28 (d, J = 5.3 Hz, 2H),3.77 (t, J = 6.7 Hz, 2H), 3.37 (d, J = 12.0 Hz, 2H), 3.05 (q, J = 11.6Hz, 2H), 2.79 (q, J = 6.8 Hz, 2H), 2.61 (d, J = 6.6 Hz, 2H), 2.39 (s,1-(5-((1-(2-methylbenzyl)piperidin-4- 3H), 1.96-1.67 (m, 3H),yl)methyl)pyrazolo[1,5-a]pyridin-3- 1.45 (q, J = 12.9 Hz, 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 42

450.4 (500 MHz, DMSO-d6) δ 10.44 (d, J = 16.3 Hz, 1H), 8.59 (d, J = 7.6Hz, 1H), 8.00 (d, J = 3.3Hz, 1H), 7.54-7.21 (m, 4H), 6.78 (d, J = 7.6Hz, 1H), 4.33 (t, J = 4.3 Hz, 2H), 3.77 (d, J = 8.0 Hz, 3H), 3.12-2.93(m, 1H), 2.78 (d, J = 8.0 Hz, 2H), 2.61 (s, 2H), 2.35 (d, J = 17.2 Hz,1H), 2.28 (s, 3H), 2.08 (d, J = 3.2 Hz, 1H), 1.96-1.67 (m, 3H),1-(5-((1-(3-fluoro-2-methylbenzyl)piperidin- 1.42 (d, J = 13.4 Hz,4-yl)methyl)pyrazolo[1,5-a]pyridin-3- 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 43

3923 (500 MHz, Methanol-d4) δ 8.34 (d, J = 7.2 Hz, 1H), 7.91 (s, 1H),7.27 (t, J = 1.3 Hz, 1H), 6.73 (dd, J = 7.1, 1.9 Hz, 1H), 6.30 (tt, J =53.4, 3.6 Hz, 1H), 3.79 (t, J = 6 8 Hz, 2H), 3.57 (q, J = 14.1, 13.3 Hz,4H), 3.06 (s, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.61 (d, J = 6.9 Hz, 2H),1.87 (q, J = 1-(5-((1-(2,2-difluoroethyl)piperidin-4- 13.3, 8.7 Hz, 3H),1.52 yl)methyl)pyrazolo[1,5-a]pyridin-3- (d, J = 13.6 Hz, 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 44

454.3 (500 MHz, DMSO-d6) δ 10.44 (d, J = 12.0 Hz, 1H), 8.59 (t, J = 7.9Hz, 1H), 8.07-7.94 (m, 1H), 7.40 (t, J = 8.7 Hz, 1H), 7.36 (s, 1H), 7.28(d, J = 7.0 Hz, 2H), 6.78 (d, J = 7.3 Hz, 1H), 4.29 (d, J = 5.0 Hz, 2H),3.76 (t, J = 6.6 Hz, 2H), 3.18 (s, 1H), 2.89 (q, J = 11.4, 8.6 Hz, 2H),2.78 (t, J = 1-(5-((1-(3,5-difluorobenzyl)piperidin-4- 6.7 Hz, 3H),2.65-2.57 yl)methyl)pyrazolo[1,5-a]pyridin-3- (m, 2H), 1.81 (q, J =yl)dihydropyrimidine-2,4(1H,3H)-dione 21.9, 19.6 Hz, 3H), 1.43 (q, J =13.1 Hz, 2H). 45

454.3 (500 MHz, DMSO-d6) δ 10.44 (d, J = 13.2 Hz, 1H), 8.58 (d, J = 7.3Hz, 1H), 8.01 (d, J = 7.1Hz, 1H), 7.58 (dt, J = 17.9, 8.9 Hz, 2H), 7.36(s, 2H), 6.78 (d, J = 7.5 Hz, 1H), 4.27 (d, J = 5.0 Hz, 2H), 3.76 (t, J= 6.7 Hz, 2H), 3.34 (s, 2H), 2.89 (d, J = 11.7 Hz, 2H), 2.78 (t, J = 6.6Hz, 2H), 1-(5-((1-(3,4-difluorobenzyl)piperidin-4- 2.66-2.57 (m, 2H),1.98- yl)methyl)pyrazolo[1,5-a]pyridin-3- 1.69 (m, 3H), 1.50-yl)dihydropyrimidine-2,4(1H,3H)-dione 1.29 (m, 2H). 46

433.2 (500 MHz, DMSO-d6) 6 10.42 10.42 (s, 1H), 8.66- 8.46 (m, 2H), 8.00(s, 1H), 7.82 (dd, J = 8.0, 2.3 Hz, 1H), 7.49-7.30 (m, 2H), 6.87-6.58(m, 1H), 4.28 (d, J = 4.5 Hz, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.36 (d, J= 13.0 Hz, 3H), 3.18 (s, 2H), 2.89 (dd, J = 14.6, 8.6 Hz, 2H), 2.78 (t,J = 6.7 Hz, 1-(5-((1-((6-methylpyridin-3- 2H), 2.59 (d, J = 6.5 Hz,yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5- 2H), 1.80 (dt, J = 32.7,a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- 15.1 Hz, 3H), 1.38 (q, J =dione 12.2 Hz, 2H). 47

432.3 (500 MHz, DMSO-d6) δ 10.44 (d, J = 15.3 Hz, 1H), 9.18 (s, 1H),8.59 (dd, J = 11.1, 7.2 Hz, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.41-7.35 (m,2H), 7.28 (d, J = 7.8 Hz, 2H), 6.84-6.71 (m, 1H), 4.21 (d, J = 5.0 Hz,2H), 3.76 (t, J = 6.7 Hz, 2H), 3.33 (d, J = 12.1 Hz, 2H), 2.87 (q, J =11.7 1-(5-((1-(4-methylbenzyl)piperidin-4- Hz, 2H), 2.78 (q, J = 6.8yl)methyl)pyrazolo[1,5-a]pyridin-3- Hz, 2H), 2.59 (d, J = 6.5yl)dihydropyrimidine-2,4(1H,3H)-dione Hz, 2H), 2.37-2.31 (m, 3H),1.92-1.64 (m, 3H), 1.39 (q, J = 12.8 Hz, 2H). 48

450.2 (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.58 (dd, J = 11.5, 7.2 Hz,1H), 8.00 (d, J = 7.0 Hz, 1H), 7.54 (dq, J = 14.8, 7.3 Hz, 1H),7.46-7.24 (m, 4H), 6.85-6.60 (m, 1H), 4.56-4.46 (m, 1H), 3.76 (d, J =6.7 Hz, 2H), 3.62 (d, J = 12.1 Hz, 1H), 3.22 (d, J = 13.1 Hz, 1H),2.83-2.63 (m, 4H), 2.58 (d, J = 6.3 Hz, 2H), 1.92-1.70 (m, 3H),1-(5-((1-(1-(3-fluorophenyl)ethyl)piperidin-4- 1.62 (d, J = 6.9 Hz, 3H),yl)methyl)pyrazolo[1,5-a]pyridin-3- 1.43 (dt, J = 40.7, 12.9yl)dihydropyrimidine-2,4(1H,3H)-dione Hz, 2H). 49

342.2 (500 MHz, DMSO-d6) δ 10.45 (d, J = 7.0 Hz, 1H), 8.60 (dt, J = 7.2,2.1 Hz, 1H), 8.01 (d, J = 3.3 Hz, 1H), 7.55- 7.08 (m, 1H), 6.80 (dd, J =7.1, 1.9 Hz, 1H), 3.77 (t, J = 6.7 Hz, 2H), 3.40 (d, J = 12.1 Hz, 2H),2.94- 2.77 (m, 4H), 2.74 (d, J = 4.8 Hz, 3H), 2.60 (d, J = 6.5 Hz, 2H),1.92- 1-(5-((1-methylpiperidin-4- 1.68 (m, 3H), 1.39 (q, J =yl)methyl)pyrazolo[1,5-a]pyridin-3- 12.4, 11.7 Hz, 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 50

454.4 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.01(s, 1H), 7.64 (td, J = 8.6, 6.5 Hz, 1H), 7.47-7.38 (m, 1H), 7.37 (s,1H), 7.26 (td, J = 8.5, 2.7 Hz, 1H), 6.78 (dd, J = 7.1, 1.9 Hz, 1H),4.31 (d, J = 4.6 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.39 (d, J = 11.8Hz, 2H), 2.97 (q, J = 11.8 Hz, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.60 (d, J= 1-(5-((1-(2,4-difluorobenzyl)piperidin-4- 6.6 Hz, 2H), 1.82 (q, J =yl)methyl)pyrazolo[1,5-a]pyridin-3- 18.9, 16.6 Hz, 3H),yl)dihydropyrimidine-2,4(1H,3H)-dione 1.57-1.31 (m, 2H) 51

504.4 (500 MHz, DMSO-d6) δ 10.36 (d, J = 11.7 Hz, 1H), 8.60-8.41 (m,1H), 7.92 (d, J = 2.9 Hz, 1H), 7.90-7.56 (m, 3H), 7.29 (s, 1H), 6.70 (d,J = 7.6 Hz, 1H), 4.31 (s, 2H), 3.69 (d, J = 7.8 Hz, 2H), 3.12 (d, J =15.6 Hz, 1H), 2.84 (t, J = 11.8 Hz, 2H), 2.69 (d, J = 7.6 Hz, 2H),2.59-2.48 (m, 2H), 1-(5-((1-(3-fluoro-5- 1.86-1.56 (m, 4H), 1.33(trifluoromethyl)benzyl)piperidin-4- (q, J = 13.4, 12.9 Hz,yl)methyl)pyrazolo[1,5-a]pyridin-3- 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 52

453.4 (400 MHz, CD₃OD) δ 8.43 (d, J = 7.2 Hz, 1H), 8.31 (s, 2H), 8.00(s, 1H), 7.36 (s, 1H), 7, 6.83 (d, J = 7.6 Hz, 1H), 4.10 (s, 2H), 3.88(t, J = 6.4 Hz, 2H), 3.57-3.50 (m, 4H), 3.37-3.34 (m, 2H), 2.96-2.86 (m,4H), 2.70 (d, J = 7.2 Hz, 2H), 1.93-1.89 (m, 3H), 1.69- 1.56 (m, 7H).1-(5-((1-(2-oxo-2-(piperidin-1-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione 53

454.4 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.58 (d, J = 7.2 Hz, 1H), 8.00(s, 1H), 7.68-7.55 (m, 1H), 7.37 (d, J = 16.6 Hz, 3H), 6.83-6.72 (m,1H), 4.37 (s, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.42 (s, 3H), 3.00 (d, J =11.6 Hz, 1H), 2.78 (t, J = 6.6 Hz, 2H), 2.59 (d, J = 6.5 Hz, 2H), 1.82(d, J = 14.7 Hz, 3H), 1.41 (d, J = 13.0 Hz, 2H).1-(5-((1-(2,3-difluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 54

487.1 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.87 (d, J = 2.1 Hz, 1H), 8.59(d, J = 7.1 Hz, 1H), 8.22 (dd, J = 8.1, 2.1 Hz, 1H), 8.06 (d, J = 8.1Hz, 1H), 8.01 (s, 1H), 7.46-7.21 (m, 1H), 6.79 (dd, J = 7.2, 1.9 Hz,1H), 4.45 (s, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.42 (d, J = 11.9 Hz, 2H),2.96 (s, 2H), 1-(5-((1-((6-(trifluoromethyl)pyridin-3- 2.79 (t, J = 6.7Hz, 2H), yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5- 2.60 (d, J = 6.6Hz, 2H), a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- 1.98-1.73 (m, 3H),1.53- dione 1.21 (m, 2H). 55

450.1 (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.00(d, J = 1.7 Hz, 1H), 7.38 (s, 1H), 6.87-6.47 (m, 1H), 3.77 (t, J = 6.7Hz, 2H), 3.62-3.35 (m, 4H), 3.29 (s, 1H), 2.94 (d, J = 11.5 Hz, 1H),2.78 (t, J = 6.7 Hz, 2H), 2.61 (d, J = 6.1 Hz, 2H), 1.92-1.71 (m, 3H),1.52 (t, J = 13.3 1-(5-((1-((1- Hz, 2H), 1.16 (d, J = 42.2(trifluoromethyl)cyclopropyl)methyl)piperidin- Hz, 4H).4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 56

502.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 15.5 Hz, 1H), 8.59 (d, J = 7.1Hz, 1H), 8.01 (s, 1H), 7.73- 7.59 (m, 2H), 7.50 (d, J = 8.2 Hz, 2H),7.37 (s, 1H), 6.87-6.71 (m, 1H), 4.32 (d, J = 5.0 Hz, 2H), 3.77 (t, J =6.7 Hz, 2H), 3.36 (d, J = 12.0 Hz, 2H), 3.00-2.89 (m, 2H), 2.79 (t, J =6.7 Hz, 2H), 1-(5-((1-(4- 2.60 (d, J = 6.5 Hz, 2H),(trifluoromethoxy)benzyl)piperidin-4- 1.94-1.68 (m, 3H), 1.41yl)methyl)pyrazolo[1,5-a]pyridin-3- (q, J = 13.1 Hz, 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 57

486.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.01(s, 1H), 7.87 (d, J = 8.0Hz, 2H), 7.81-7.69 (m, 2H), 7.37 (s, 1H),6.89-6.68 (m, 1H), 4.39 (d, J = 4.8 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H),3.37 (d, J = 12.0 Hz, 2H), 2.93 (q, J = 11.7 Hz, 2H), 2.78 (t, J = 6.7Hz, 2H), 2.60 (d, J = 1-(5-((1-(4-(trifluoromethyl)benzyl)piperidin- 6.5Hz, 2H), 1.96-1.30- 4-yl)methyl)pyrazolo[1,5-a]pyridin-3- 1.65 (m, 3H),1.52-1.30 yl)dihydropyrimidine-2,4(1H,3H)-dione (m, 2H). 58

450.4 (500 MHz, DMSO-d6) δ 10.44 (d, J = 13.8 Hz, 1H), 8.59 (d, J = 7.7Hz, 1H), 8.00 (d, J = 2.9 Hz, 1H), 7.35 (d, J = 10.7 Hz, 3H), 7.22 (d, J= 9.0 Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 4.28 (s, 2H), 3.76 (t, J = 6.8Hz, 2H), 3.05 (d, J = 12.0 Hz, 3H), 2.78 (d, J = 7.5 Hz, 2H), 2.61 (d, J= 6.5 Hz, 2H), 2.34 (s, 3H), 2.08 (d, J = 3.0 Hz, 1H), 1.811-(5-((1-(5-fluoro-2-methylbenzyl)piperidin- (q, J = 18.9, 17.5 Hz,4-yl)methyl)pyrazolo[1,5-a]pyridin-3- 3H), 1.56-1.27 (m, 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 59

452.4 (500 MHz, DMSO-d6) δ 10.44 (d, J = 13.7 Hz, 1H), 8.58 (d, J = 7.8Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 7.64 (dd, J = 31.9, 7.8 Hz, 2H), 7.51(q, J = 8.4 Hz, 2H), 7.35 (s, 1H), 6.88-6.61 (m, 1H), 4.40 (d, J = 4.9Hz, 2H), 3.77 (d, J = 7.7 Hz, 3H), 3.08 (d, J = 11.7 Hz, 2H), 2.78 (d, J= 7.2 Hz, 2H), 2.69-2.55 (m, 2H), 2.08 (d, J = 2.7 Hz, 1H),1-(5-((1-(2-chlorobenzyl)piperidin-4- 1.95-1.76 (m, 3H), 1.53-yl)methyl)pyrazolo[1,5-a]pyridin-3- 1.33 (m, 2H).yl)dihydropyrimidine-2,4(1H,3H)-dione 60

425.4 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.59 (d, J = 7.1 Hz, 1H), 8.00(d, J = 4.0 Hz, 2H), 7.95(d, J = 3.2 Hz, 1H), 7.38 (d, J = 1.4 Hz, 1H),6.79 (dd, J = 7.2, 1.9 Hz, 1H), 4.72 (s, 2H), 3.77 (t, J = 6.7 Hz, 2H),3.51 (d, J = 12.1 Hz, 2H), 3.02 (s, 2H), 2.79 (t, J = 6.7 Hz, 2H), 2.60(d, J = 6.4 Hz, 1-(5-((1-(thiazol-2-ylmethyl)piperidin-4- 2H), 1.83 (d,J = 14.2 Hz, yl)methyl)pyrazolo[1,5-a]pyridin-3- 3H), 1.47 (d, J = 13.5yl)dihydropyrimidine-2,4(1H,3H)-dione Hz, 2H). 61

448.2 (500 MHz, DMSO-d6) δ 10.45 (d, J = 16.0 Hz, 1H), 8.60 (dd, J =11.3, 7.2 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.42-7.35 (m, 3H), 7.03(dq, J = 9.5, 7.7, 7.1 Hz, 3H), 4.20 (d, J = 5.2 Hz, 2H), 3.82-3.74 (m,4H), 3.34 (d, J = 12.0 Hz, 2H), 2.86 (q, J = 12.8, 12.0 Hz, 2H), 2.78(t, J = 6.8 1-(5-((1-(4-methoxybenzyl)piperidin-4- Hz, 2H), 2.60 (d, J =6.4 yl)methyl)pyrazolo[1,5-a]pyridin-3- Hz, 2H), 1.87-1.71 (m,yl)dihydropyrimidine-2,4(1H,3H)-dione 3H), 1.50-1.18 (m, 3H). 62

452.0 (400 MHz, CD₃OD) δ 8.44 (d, J = 7.2 Hz, 1H), 8.01 (s, 1H), 7.38(s, 1H), 6.84 (d, J = 7.2 Hz, 1H), 3.89 (t, J = 6.8 Hz, 2H), 3.65 (s,1H), 3.48 (s, 1H), 3.37-3.33 (m, 2H), 3.16-3.13 (m 2H), 2.89 (t, J = 6.8Hz, 2H), 2.77-2.69 (m, 2H), 2.01- 1.90 (m, 3H), 1.70-1.67 (m, 2H), 1.36(s, 6H) ppm. 1-(5-((1-(3,3,3-trifluoro-2,2- NH proton not observeddimethylpropyl)piperidin-4- due to solventyl)methyl)pyrazolo[1,5-a]pyridin-3- exchange.yl)dihydropyrimidine-2,4(1H,3H)-dione

Example 63. Preparation of1-(5-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,401H,3H)-dione (Example 63)

Prepared by the method of Example 1 using tert-butyl4-(bromomethyl)piperidine-1-carboxylate in step 4 in place of(bromomethyl)cyclohexane. LCMS [M+H]⁺: 425.2. ¹H NMR (500 MHz, DMSO-d6)δ 10.45 (d, J=6.6 Hz, 1H), 8.61 (dd, J=7.2, 3.9 Hz, 1H), 8.40 (d, J=11.9Hz, 1H), 8.02 (d, J=3.2 Hz, 1H), 7.47-7.35 (m, 1H), 6.80 (dd, J=7.2, 1.9Hz, 1H), 3.78 (td, J 6.7, 4.0 Hz, 2H), 3.51 (d, J=11.8 Hz, 2H), 3.30 (d,J=12.8 Hz, 2H), 2.98 (t, J=6.1 Hz, 2H), 2.94-2.82 (m, 4H), 2.79 (t,J=6.7 Hz, 2H), 2.62 (d, J=6.6 Hz, 2H), 2.09 (dt, J=7.7, 3.8 Hz, 1H),1.84 (dq, J=29.1, 16.0, 14.5 Hz, 5H), 1.50 (q, J=13.1 Hz, 2H), 1.41-1.28(in, 2H).

Examples 64 and 65. Preparation of1-(5-((1-(((1r,4r)-4-methoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 64) and1-(5-((1-(((1s,4s)-4-methoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 65)

Prepared by the method of Example 1 using a commercially availablemixture of cis and trans 1-(bromomethyl)-4-methoxycyclohexane in step 4in place of (bromomethyl)cyclohexane. The stereoisomers were purifiedafter step 5 by reverse-phase HPLC (eluting with using ACN/Water/0.1%TFA).

Example 64.1-(5-((1-(((1r,4r)-4-methoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Eluted first, minor isomer. LCMS [M+H]⁺: 454.3. ¹H NMR (500 MHz,DMSO-d6) δ 10.45 (d, J=4.6 Hz, 1H), 8.60 (d, J=7.1 Hz, 1H), 8.01 (s,1H), 7.47-7.27 (m, 1H), 6.80 (dd, J=7.1, 1.9 Hz, 1H), 3.78 (td, J=6.7,3.0 Hz, 2H), 3.47 (d, J=12.1 Hz, 2H), 3.24 (d, J=5.2 Hz, 4H), 3.05 (ddt,J=16.9, 10.7, 5.3 Hz, 1H), 2.93-2.83 (m, 3H), 2.79 (t, J=6.7 Hz, 2H),2.62 (d, J=6.6 Hz, 2H), 2.00 (d, J=12.3 Hz, 2H), 1.92-1.63 (m, 6H), 1.49(q, J=13.1 Hz, 2H), 1.19-1.07 (m, 2H), 0.98 (q, J=12.9 Hz, 2H).

Example 65.1-(5-((1-(((1s,4s)-4-methoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Eluted second, major isomer. LCMS [M+H]⁺: 454.3. ¹H NMR (500 MHz,Methanol-d4) δ 8.45 (d, J=7.1 Hz, 1H), 8.02 (s, 1H), 7.49-7.25 (m, 1H),6.85 (dd, J=7.1, 1.8 Hz, 1H), 3.90 (t, J=6.8 Hz, 2H), 3.61-3.44 (m, 3H),3.35 (s, 3H), 2.92 (dt, J=13.6, 6.9 Hz, 6H), 2.71 (d, J=7.1 Hz, 2H),2.09-1.82 (m, 6H), 1.70-1.46 (m, 6H), 1.44-1.31 (m, 2H).

Example 66. Preparation of1-(5-(((1R,5S)-8-(cyclohexylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared by the method of Example 1, steps 2-5 using tert-butyl(1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate in step 2 inplace of tert-butyl 4-methylenepiperidine-1-carboxylate. LCMS [M+H]⁺:450.4. ¹H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.53-8.52 (m, 1H),8.29-8.20 (m, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.42-7.29 (m, 1H), 6.77 (d,J=7.2 Hz, 1H), 3.75-3.60 (m, 2H), 3.23 (br s, 2H), 2.84-2.70 (m, 3H),2.24 (br s, 2H), 2.11-1.82 (m, 4H), 1.81-1.56 (m, 6H), 1.56-1.37 (m,4H), 1.33-1.09 (m, 4H), 0.91-0.78 (m, 2H).

Example 67. Preparation of1-(5-(((1R,5S)-8-isobutyl-8-azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared by the method of Example 1, steps 2-5 using tert-butyl(1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate in step 2 inplace of tert-butyl 4-methylenepiperidine-1-carboxylate, and1-iodo-2-methylpropane in step 4 in place of (bromomethyl)cyclohexane.LCMS [M+H]⁺: 410.3. ¹H NMR (400 MHz, CDCl₃) ppm 11.33 (s, 1H), 8.40 (m,J=6.8 Hz, 1H), 7.94 (s, 1H), 7.75 (s, 1H), 6.67 (m, J=7.3, 11.7 Hz, 1H),3.93-3.84 (m, 4H), 3.19 (s, 1H), 2.97-2.89 (m, 3H), 2.78-2.71 (m, 4H),2.42-2.25 (m, 2H), 2.15 (s, 1H), 1.92 (m, J=8.6 Hz, 2H), 1.68 (s, 3H),1.14 (m J=6.4 Hz, 6H).

Example 68. Preparation of1-(5-(((1R,5S)-8-(pyridin-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared by the method of Example 1, steps 2-5 using tert-butyl(1R,5S)-3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate in step 2 inplace of tert-butyl 4-methylenepiperidine-1-carboxylate, and3-(bromomethyl)pyridine in step 4 in place of (bromomethyl)cyclohexane.LCMS [M+H]⁺: 445.3. ¹H NMR 1H NMR (400 MHz, METHANOL-d4) ppm=8.54 (s,1H), 8.46-8.34 (m, 2H), 8.00-7.96 (m, 1H), 7.89 (m, J=7.8 Hz, 1H),7.44-7.30 (m, 2H), 6.81 (d, J=2.1, 7.1 Hz, 1H), 3.88 (dt, J=4.6, 6.7 Hz,2H), 3.60 (d, J=4.4 Hz, 2H), 3.18 (s, 2H), 2.89 (m, 3H), 2.58 (d, J=7.2Hz, 1H), 2.23-2.17 (m, 1H), 2.10-2.03 (m, 2H), 1.94-1.81 (m, 1H),1.68-1.60 (m, 1H), 1.49 (d, J=2.7, 8.7 Hz, 2H), 1.41 (m, J=13.9 Hz, 1H).

Example 69. Preparation of1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.3-(2,4-dimethoxybenzyl)-1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To a stirred solution of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (100 mg, 0.209 mmol) and 2-chloro-4-methoxypyrimidine(30.2 mg, 0.209 mmol) in MeCN (1 mL) was added DIPEA (54 mL, 0.418mmol). The mixture was stirred for 2 h at 120° C. After completion, thereaction was cooled to rt and diluted with EtOAc and water. The organiclayer was dried over Na₂SO₄ and concentrate. The crude compound waspurified by silica gel chromotography (eluting with 10% MeOH in DCM) toafford3-(2,4-dimethoxybenzyl)-1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(90 mg, 0.153 mmol, 90% yield). LCMS [M+H]⁺: 586.3.

Step 2.1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To a stirred solution of3-(2,4-dimethoxybenzyl)-1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(90 mg, 0.145 mmol) in TFA (1 mL) was added TfOH (0.1 mL) and thereaction mixture was stirred at 70° C. for 2 h. After completion, thereaction was concentrate. The crude compound was purified by PREP HPLCusing: Mobile Phase: A=0.1% HCOOH in water, B=Acetonitrile, Column:JUPITER Phenomenex (250 mm×21.2 mm), 5.0 μm, Flow: 20 mL/min. thecollected fraction were concentrated under reduced pressure to afford1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(25 mg, 0.053 mmol, 27% yield) as an off-white solid. LCMS [M+H]⁺:436.2; HPLC: Rt=4.794 min. ¹H NMR (400 MHz, Methanol-d4) δ 8.43 (d,J=7.1 Hz, 1H), 8.00 (s, 1H), 7.96 (d, J=6.4 Hz, 1H), 7.37 (s, 1H), 6.85(dd, J=7.1, 1.8 Hz, 1H), 6.21 (d, J=6.5 Hz, 1H), 4.56 (d, J=9.6 Hz, 2H),3.89 (t, J=6.8 Hz, 2H), 3.05 (t, J=12.9 Hz, 2H), 2.89 (t, J=6.8 Hz, 2H),2.68 (d, J=7.3 Hz, 2H), 2.10-1.97 (m, 1H), 1.83 (d, J=13.2 Hz, 2H), 1.33(qd, J=12.3, 3.3 Hz, 3H), NH proton not observed due to solventexchange.

Example 70. Preparation of1-(5-((1-(3-methylbutan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. 1-(3-methylbutan-2-yl)-4-methylenepiperidine

To a solution of 4-methylenepiperidine hydrochloride (2.0 g, 15 mmol) inDCM (20 mL) was added TEA (6.25 mL 44.9 mmol), TiCl4 (0.8 mL 7.48 mmol)and 3-methylbutan-2-one (1.4 g, 16.5 mmol). The mixture was stirred atrt for 12 h and then NaBH₃CN (2.8 g, 45 mmol) was added. The reactionwas stirred for 4 h at rt. After completion, the mixture was dilutedwith DCM and washed with water. The organic layer was dried over Na₂SO₄,filtered and concentrated to obtain1-(3-methylbutan-2-yl)-4-methylenepiperidine (0.4 g, crude). ¹H NMR (300MHz, CDCl₃) b 4.60 (s, 2H), 2.61-2.53 (m, 2H), 2.36-2.31 (m, 2H),2.25-2.09 (m, 4H), 1.65-1.59 (m, 1H), 1.11-1.06 (m, 3H), 0.96-0.92 (m,3H), 0.89-0.85 (m, 3H).

Step 2.1-(5-((1-(3-methylbutan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 70) was prepared from1-(3-methylbutan-2-yl)-4-methylenepiperidine using the method of Example1, steps 2 and 5, wherein 1-(3-methylbutan-2-yl)-4-methylenepiperidinewas used in place of tert-butyl 4-methylenepiperidine-1-carboxylate.LCMS [M+H]⁺: 398.3. ¹H NMR (300 MHz, CD₃OD) δ 8.42 (d, J=7.2 Hz, 1H),8.00 (s, 1H), 7.35 (s, 1H), 6.82 (dd, J=7.2 Hz, 1.2 Hz, 1H), 3.87 (t,J=6.4 Hz, 2H), 3.58-3.47 (m, 2H), 3.13-2.96 (m, 3H), 2.87 (t, J=6.8 Hz,2H), 2.69 (d, J=6.4 Hz, 2H), 2.24-2.20 (m, 1H), 1.98-1.94 (m, 3H),1.59-1.55 (m, 2H), 1.27 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 0.98(d, J=6.8 Hz, 3H), NH proton not observed due to solvent exchange.

Example 71. Preparation of1-(5-(((2S,4S)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl (S)-2-methyl-4-methylenepiperidine-1-carboxylate.

To dry t-BuOK (1.58 g, 14.1 mmol) in THF (20 mL) was addedmethyltriphenylphosphonium bromide (5.02 g, 14.07 mmol) at 0° C., thenthe mixture was stirred at rt for 2 h. The mixture was cooled to 0° C.and a solution of tert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate(2 g, 9.38 mmol) in THF (5 mL) was added slowly. The reaction mixturewas stirred at rt for 14 h. The reaction mixture was quenched with asolution of saturated aqueous NH₄Cl (50 mL) and extracted with EtOAc(2×). The combined organic layers were concentrated to give the crudeproduct. The crude product was purified by flash silica gelchromatography (eluted with 0-10% EtOAc/petroleum ether) to givetert-butyl (S)-2-methyl-4-methylenepiperidine-1-carboxylate (1.7 g, 8.1mmol, 86% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 4.85 (d,J=1.6 Hz, 1H), 4.74 (d, J=1.6 Hz, 1H), 4.51-4.48 (m, 1H), 4.04-4.01 (m,1H), 2.89-2.82 (m, 1H), 2.42-237 (m, 1H), 2.17-2.13 (m, 2H), 2.03-2.00(m, 1H), 1.47 (s, 9H), 1.07 (d, J=6.8 Hz, 3H).

Step 2.1-(5-(((2S,4S)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 71) was prepared from tert-butyl(S)-2-methyl-4-methylenepiperidine-1-carboxylate using the method ofExample 1, steps 2 to 5, wherein tert-butyl(S)-2-methyl-4-methylenepiperidine-1-carboxylate was used in place oftert-butyl 4-methylenepiperidine-1-carboxylate. The final productcontained a minor amount of the trans isomer which was removed by SFCpurification: Column: Chiralpak IG-3 50×4.6 mm I.D., 3 μm Mobile phase:Phase A for CO₂, and Phase B for IPA (0.05% DEA); Gradient elution: 40%IPA (0.05% DEA) in CO₂ Flow rate: 3 mL/min; Detector: PDA Column Temp:35° C.; Back Pressure: 100 Bar. Product is peak 1, retention time 3.1min. LCMS [M+H]⁺: 438.3. ¹H NMR (400 MHz, METHANOL-d4) δ 8.40 (d, J=7.2Hz, 1H), 7.98 (s, 1H), 7.33 (s, 1H), 6.81-6.79 (m, 1H), 3.89-3.86 (m,2H), 3.04 (br d, J=12.0 Hz, 1H), 2.89-2.87 (m, 2H), 2.66-2.56 (m, 3H),2.20-1.84 (m, 4H), 1.75-1.44 (m, 8H), 1.37-1.11 (m, 5H), 1.10-1.03 (m,3H), 0.99-0.81 (m, 2H).

The compounds in the following table were prepared by the method ofExample 71, using the appropriate commercially available halide in thealkylation step.

Example Mass No. Structure [M + H]⁺ ¹H NMR 72

398.3 (400 MHz, CD₃OD) δ 8.44 (d, J = 7.2 Hz, 1H), 8.37 (s, 1H), 8.01(s, 1H), 7.37 (s, 1H), 6.84 (dd, J = 6.8 Hz, 1.2 Hz, 1H), 3.89 (t, J =6.4 Hz, 2H), 3.62-3.60 (m, 1H), 3.20-3.14 (m, 3H), 2.92-2.87 (m, 3H),2.84-2.79 (m, 1H), 2.70-2.66 (m, 3H), 2.10-2.05 (m, 2H), 1.93-1.90 (m,2H), 1.55-1.45 (m, 2H), 1.37 (d, J = 6.4 Hz, 1H), 1.07-1.02 (m, 6H). 73

440.1 (400 MHz, CD₃OD) δ 8.44 (d, J = 7.2 Hz, 1H), 8.29 (s, 1H), 8.01(s, 1H), 7.37 (s, 1H), 6.84 (dd, J = 7.2 Hz, 1.6 Hz, 1H), 3.98-3.94 (m,2H), 3.89 (t, J = 6.4 Hz, 2H), 3.68-3.62 (m, 1H), 3.48-3.42 (m, 2H),3.28-3.24 (m, 2H), 3.02-2.98 (m, 1H), 2.90-2.84 (m, 3H), 2.70-2.66 (m,2H), 2.08-2.06 (m, 2H), 1.94-1.90 (m, 2H), 1.75-1.73 (m, 1H), 1.65-1.63(m, 1H), 1.51-1.36 (m, 7H). 74

474.2 (400 MHz, CD₃OD) δ 8.43 (d, J = 6.4 Hz, 2H), 7.99 (s, 1H), 7.35(s, 1H), 6.82 (dd, J = 6.8 Hz, 1.6 Hz, 1H), 3.89 (t, J = 6.8 Hz, 2H),3.62-3.58 (m, 1H), 3.24-3.20 (m, 2H), 2.98-2.85 (m, 4H), 2.68 (d, J =6.8 Hz, 1H), 2.07-2.04 (m, 3H), 1.91-1.81 (m, 7H), 1.42-1.33 (m, 7H).

The compounds in the following table were prepared using the method ofExample 71, wherein tert-butyl(R)-2-methyl-4-oxopiperidine-1-carboxylate was used in place oftert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and, using theappropriate commercially available halide in the alkylation step.

Example Mass No. Structure [M + H]⁺ ¹H NMR 75

440.2 (400 MHz, Methanol-d4) δ 8.43 (d, J = 7.0 Hz, 1H), 8.35 (s, 1H),8.00 (s, 1H), 7.36 (s, 1H), 6.82 (d, J = 7.1 Hz, 1H), 3.95 (dd, J =11.8, 4.3 Hz, 2H), 3.88 (t, J = 6.7 Hz, 2H), 3.64 (s, 1H), 3.50-3.37 (m,3H), 3.02 (d, J = 82.6 Hz, 5H), 2.88 (t, J = 6.8 Hz, 2H), 2.69 (d, J =7.1 Hz, 2H), 1.99 (d, J = 53.6 Hz, 4H), 1.68 (dd, J = 37.8, 12.9 Hz,2H), 1.56-1.31 (m, 8H). NH proton not observed due to solvent exchange76

438.2 (400 MHz, Methanol-d4) δ 8.43 (d, J = 7.2 Hz, 1H), 8.01 (s, 1H),7.36 (d, J = 1.7 Hz, 1H), 6.83 (dd, J = 7.3, 1.9 Hz, 1H), 3.89 (t, J =6.8 Hz, 2H), 3.59 (d, J = 12.6 Hz, 1H), 3.27-3.09 (m, 2H), 2.89 (t, J =6.7 Hz, 3H), 2.77 (dd, J = 13.3, 5.2 Hz, 1H), 2.72-2.61 (m, 3H), 2.05(ddq, J = 11.9, 7.6, 3.8 Hz, 1H), 1.98-1.65 (m, 7H), 1.64-1.16 (m, 8H),1.05 (dd, J = 16.5, 7.2 Hz, 2H). NH proton not observed due to solventexchange 77

398.2 (400 MHz, CD₃OD) δ 8.50 (s, 1H), 8.43 (d, J = 7.2 Hz, 1H), 7.99(s, 1H), 7.34 (s, 1H), 6.81 (dd, J = 7.2, 1.6 Hz, 1H), 3.87 (t, J = 7.2Hz, 2H), 3.52-3.48 (m, 1H), 3.34 (m, 1H), 3.08-3.02 (m, 1H), 2.87 (t, J= 7.2 Hz, 2H), 2.80-2.74 (m, 1H), 2.67 (d, J = 6.8 Hz, 2H), 2.04-1.84(m, 4H), 1.50-1.37 (m, 3H), 1.30 (d, J = 6.0 Hz, 3H), 1.01 (t, J = 6.4Hz, 6H). 78

474.4 (400 MHz, Methanol-d4) δ 8.40 (d, J = 7.1 Hz, 1H), 7.98 (s, 1H),7.34 (s, 1H), 6.81 (dd, J = 7.3, 1.8 Hz, 1H), 3.88 (t, J = 6.7 Hz, 2H),3.06 (d, J = 11.6 Hz, 1H), 2.89 (t, J = 6.8 Hz, 2H), 2.65 (d, J = 11.8Hz, 1H), 2.60 (d, J = 7.1 Hz, 2H), 2.19 (t, J = 7.5 Hz, 1H), 2.12-1.90(m, 5H), 1.84-1.54 (m, 6H), 1.40-1.11 (m, 5H), 1.08 (d, J = 6.3 Hz, 3H).

Example 79. Preparation of1-(5-((1-isobutyl-2,2-dimethylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 71 wherein tert-butyl2,2-dimethyl-4-oxopiperidine-1-carboxylate was used in place oftert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate. LCMS [M+H]⁺:412.6. ¹H NMR (400 MHz, CD30D) δ 8.44 (d, J=7.2 Hz, 1H), 8.39 (s, 1H),8.02 (s, 1H), 7.36 (s, 1H), 6.85-6.83 (m, 1H), 3.90 (t, J=7.2 Hz, 2H),3.53-3.50 (m, 1H), 3.22-3.13 (m, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.67-2.65(m, 3H), 2.21 (brs, 1H), 2.03-1.82 (m, 3H), 1.65-1.52 (m, 2H), 1.43 (s,3H), 1.36 (s, 3H), 1.10-1.06 (m, 6H).

Example 80. Preparation of1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1:1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

DIPEA (0.042 mL, 0.24 mmol) and cyclohexylmethanesulfonyl chloride (14mg, 0.073 mmol) were added to a solution of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (25 mg, 0.049 mmol) in DCM (1.5 mL) at rt. The mixture wasstirred at rt for 1 h, then diluted with DCM and washed sequentiallywith water and brine. The organic layer was dried over sodium sulfate,filtered and concentrated to give crude1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(31 mg, 0.049 mmol). LCMS [M+H]⁺: 638.4.

Step 2:1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 80) was prepared from 1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione by the method of Example 1, step 5,wherein1-(5-((1-((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]: 488.3. H NMR (500 MHz, DMSO-d6) 10.44 (s, 1H), 8.57 (d,J=7.1 Hz, 1H), 8.00 (s, 1H), 7.38 (d, J=1.7 Hz, 1H), 6.80 (dd, J=7.2,1.9 Hz, 1H), 3.77 (t, J=6.7 Hz, 2H), 3.56 (d, J=12.2 Hz, 2H), 2.85 (d,J=6.2 Hz, 2H), 2.79 (t, J=6.7 Hz, 2H), 2.70 (td, J=12.1, 2.4 Hz, 2H),2.60 (d, J=6.9 Hz, 2H), 1.92-1.78 (m, 3H), 1.79-1.64 (m, 5H), 1.59 (dd,J=10.3, 6.4 Hz, 1H), 1.31-1.19 (m, 4H), 1.18-1.00 (in, 3H).

The compounds in the following table were prepared by the method ofExample 80, using the appropriate commercially available sulfonylchloride or chloroformate in step 1.

Example Mass No. Structure [M + H]⁺ ¹H NMR 81

474.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.56 (d, J = 7.0 Hz, 1H), 7.99(s, 1H), 7.38 (t, J = 1.2 Hz, 1H), 6.79 (dd, J = 7.2, 1.9 Hz, 1H), 3.77(t, J = 6.7 Hz, 2H), 3.70-3.49 (m, 2H), 3.06 (tt, J = 11.7,3.4 Hz, 1H),2.92-2.71 (m, 4H), 2.59 (d, J = 7.2 Hz, 2H), 2.09-1.92 (m, 2H),1.88-1.72 (m, 3H), 1.72-1.55 (m, 3H), 1.43-0.96 (m, 7H). 82

460.4 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.57 (d, J = 7.0 Hz, 1H), 7.99(s, 1H), 7.37 (s, 1H), 6.79 (dd, J = 7.2, 1.9 Hz, 1H), 3.77 (t, J = 6.7Hz, 2H), 3.62 (d, J = 13.3 Hz, 2H), 3.58 (d, J = 7.9 Hz, 1H, 2.82-2.74(m, 4H), 2.60 (d, J = 7.1 Hz, 2H), 1.99-1.87 (m, 2H), 1.77 (dt, J =14.1, 7.4 Hz, 3H), 1.67 (d, J = 13.0 Hz, 4H), 1.55 (t, J = 6.0 Hz, 2H),1.21 (dt, J = 21.9, 10.9 Hz, 2H). 83

476.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.57 (d, J = 7.1 Hz, 1H), 7.99(s, 1H), 7.43-7.30 (m, 1H), 6.79 (dd, J = 7.2, 1.9 Hz, 1H), 3.94-3.88(m, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.63 (d, J = 12.5 Hz, 2H), 3.39 (tt,J = 12.0, 3.8 Hz, 1H), 3.33 (td, J = 11.8, 2.0 Hz, 2H), 2.92-2.83 (m,2H), 2.79 (t, J = 6.7 Hz, 2H), 2.60 (d, J = 7.1 Hz, 2H), 1.92-1.71 (m,3H), 1.62 (dtd, J = 29.5, 13.0, 12.4, 4.1 Hz, 4H), 1.32-1.08 (m, 2H). 84

446.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.57 (d, J = 7.1 Hz, 1H), 7.99(s, 1H), 7.38 (d, J = 1.8 Hz, 1H), 6.80 (dd, J = 7.1, 1.8 Hz, 1H), 3.77(t, J = 6.7 Hz, 2H), 3.61 (d, J = 12.3 Hz, 2H), 2.97 (d, J = 7.1 Hz,2H), 2.85-2.71 (m, 4H), 2.60 (d, J = 7.0 Hz, 2H), 1.90-1.59 (m, 3H),1.22 (qd, J = 12.3, 4.2 Hz, 2H), 0.98 (dqd, J = 15.1, 7.6, 4.8 Hz, 1H),0.65-0.53 (m, 2H), 0.42-0.19 (m, 2H). 85

434.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.56 (dd, J = 7.1, 0.9 Hz,1H), 7.99 (s, 1H), 7.38 (d, J = 1.7 Hz, 1H), 6.79 (dd, J = 7.2, 1.9 Hz,1H), 3.77 (t, J = 6.7 Hz, 2H), 3.63 (d, J = 12.5 Hz, 2H), 3.29 (p, J =6.8 Hz, 1H), 2.87-2.76 (m, 4H), 2.60 (d, J = 7.2 Hz, 2H), 1.77 (t, J =4.8 Hz, 1H), 1.66 (d, J = 13.1 Hz, 2H), 1.21 (d, J = 6.8 Hz, 8H). 86

448.3 (500 MHz, Methanol-d4) δ 8.31 (dd, J = 7.2, 0.9 Hz, 1H), 7.88 (s,1H), 7.26 (dd, J = 1.9, 0.9 Hz, 1H), 6.73 (dd, J = 7.2, 1.9 Hz, 1H),3.78 (t, J = 6.8 Hz, 2H), 3.71-3.62 (m, 2H), 2.93 (ddd, J = 9.3,6.8, 3.9Hz, 1H), 2.84-2.73 (m, 4H), 2.55 (d, J = 7.3 Hz, 2H), 1.84 (dtd, J =15.2, 7.6, 4.0 Hz, 1H), 1.73 (ddt, J = 11.4, 7.6, 3.8 Hz, 1H), 1.63 (d,J = 13.3 Hz, 2H), 1.40 (ddd, J = 13.7, 9.4, 7.4 Hz, 1H), 1.18 (d, J =6.9 Hz, 5H), 0.91 (t, J = 7.5 Hz, 3H). 87

448.3 (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.56 (d, J = 7.1 Hz, 1H), 7.99(d, J = 1.7 Hz, 1H), 7.37 (s, 1H), 6.79 (d, J = 7.2 Hz, 1H), 3.76 (t, J= 6.7 Hz, 2H), 3.65-3.57 (m, 2H), 2.85 (d, J = 6.6 Hz, 2H, 2.78 (t, J =6.7 Hz, 2H), 2.70 (t, J = 11.9 Hz, 2H), 2.59 (d, J = 6.9 Hz, 2H), 2.09(hept, J = 6.6 Hz, 1H, 1.80-1.62 (m, 3H), 1.30-1.16 (m, 2H), 1.02 (dd, J= 6.8, 1.7 Hz, 6H). 88

482.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.56 (d, J = 7.1 Hz, 1H), 8.00(s, 1H), 7.50-7.26 (m, 6H), 6.78 (dd, J = 7.2, 1.9 Hz, 1H), 4.37 (s,2H), 3.77 (t, J = 6.7 Hz, 2H), 3.54 (d, J = 12.4 Hz, 2H), 2.79 (t, J =6.7 Hz, 2H), 2.67 (td, J = 12.4, 2.5 Hz, 2H), 2.57 (d, J = 7.1 Hz, 2H),1.70 (tt, J = 7.4, 3.6 Hz, 1H, 1.63 (d, J = 13.2 Hz, 2H), 1.16 (qd, J =12.2, 4.2 Hz, 2H). 89

432.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8.00(s, 1H), 7.46-7.27 (m, 1H), 6.80 (dd, J = 7.1, 1.9 Hz, 1H), 3.78 (t, J =6.7 Hz, 2H), 3.59 (d, J = 12.2 Hz, 2H), 2.84-2.73 (m, 4H), 2.61 (d, J =7.0 Hz, 2H), 2.59-2.54 (m, 1H), 1.85-1.59 (m, 3H), 1.25 (qd, J = 12.3,4.0 Hz, 2H, 1.06-0.82 (m, 4H). 90

406.3 (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.56 (dd, J = 7.1, 0.9 Hz,1H), 7.99 (s, 1H), 7.37 (dd, J = 1.9, 0.9 Hz, 1H), 6.79 (dd, J = 7.1,1.9 Hz, 1H), 3.77 (t, J = 6.7 Hz, 2H), 3.54 (d, J = 11.6 Hz, 2H), 2.83(s, 3H), 2.78 (t, J = 6.7 Hz, 2H), 2.71-2.57 (m, 4H), 1.77-1.64 (m, 3H),1.27 (t, J = 11.8 Hz, 2H). 91

468.3 (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.52 (dd, J = 7.1, 0.9 Hz,1H), 7.98 (s, 1H), 7.74-7.68 (m, 3H), 7.66-7.60 (m, 2H), 7.32 (t, J =1.4 Hz, 1H), 6.72 (dd, J = 7.2, 1.9 Hz, 1H), 3.75 (t, J = 6.7 Hz, 2H),3.65 (d, J = 12.0 Hz, 2H), 2.77 (t, J = 6.7 Hz, 2H), 2.56-2.53 (m, 2H),2.19 (td, J = 12.0, 2.3 Hz, 2H), 1.77-1.42 (m, 3H), 1.24 (td, J = 12.3,11.9, 4.0 Hz, 2H). 92

450.2 (500 MHz, Methanol-d4) δ 8.31 (dd, J = 7.2, 0.9 Hz, 1H), 7.88 (s,1H), 7.26 (dd, J = 1.9, 0.9 Hz, 1H), 6.73 (dd, J = 7.2, 1.9 Hz, 1H),3.78 (t, J = 6.8 Hz, 2H), 3.65-3.54 (m, 4H), 3.24 (s, 3H), 3.14 (t, J =5.9 Hz, 2H), 2.79 (t, J = 6.8 Hz, 2H), 2.69 (td, J = 12.3, 2.4 Hz, 2H),2.59-2.53 (m, 2H), 1.76-1.61 (m, 3H), 1.28-1.17 (m, 2H). 93

386.3 (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.54 (dd, J = 7.1, 0.9 Hz,1H), 7.98 (s, 1H), 7.35 (dd, J = 1.9, 1.0 Hz, 1H), 6.78 (dd, J = 7.1,1.9 Hz, 1H), 3.94 (d, J = 13.0 Hz, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.57(s, 3H), 2.78 (t, J = 6.7 Hz, 4H), 2.56 (d, J = 7.2 Hz, 2H), 1.85-1.76(m, 1H), 1.59 (d, J = 13.0 Hz, 2H, 1.08 (qd, J = 12.3, 4.3 Hz, 2H). 94

448.3 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.58 (dd, J = 7.1, 0.9 Hz,1H), 8.00 (s, 1H), 7.46-7.35 (m, 3H), 7.27-7.19 (m, 1H), 7.15-7.06 (m,2H), 6.82 (dd, J = 7.2, 1.9 Hz, 1H, 4.21-3.98 (m, 2H), 3.78 (t, J = 6.7Hz, 2H), 2.99 (s, 1H), 2.80 (t, J = 6.7 Hz, 3H), 2.63 (d, J = 7.2 Hz,2H), 1.88 (tt, J = 7.4, 3.7 Hz, 1H), 1.73-1.65 (m, 2H), 1.24 (s, 2H). 95

428.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.56 (d, J = 7.1 Hz, 1H), 7.99(s, 1H), 7.36 (d, J = 1.8 Hz, 1H), 6.79 (dd, J = 7.1, 1.8 Hz, 1H), 3.97(d, J = 13.2 Hz, 2H), 3.77 (dt, J = 6.7, 3.4 Hz, 5H), 2.79 (t, J = 6.7Hz, 3H), 2.57 (d, J = 7.1 Hz, 2H), 1.96-1.73 (m, 2H), 1.66-1.54 (m, 2H),1.10 (qd, J = 12.4, 4.3 Hz, 2H), 0.89 (d, J = 6.7 Hz, 6H). 96

454.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.56 (d, J = 7.1 Hz, 1H), 7.99(s, 1H), 7.36 (s, 1H), 6.79 (dd, J = 7.2, 1.9 Hz, 1H), 4.54 (dt, J =8.6, 4.5 Hz, 1H), 3.97 (d, J = 13.1 Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H),2.79 (t, J = 6.7 Hz, 4H), 2.57 (d, J = 7.2 Hz, 2H), 1.76 (d, J = 7.9 Hz,3H), 1.69-1.56 (m, 4H), 1.53-1.20 (m, 6H), 1.09 (qd, J = 12.3, 4.2 Hz,2H).

Example 97. Preparation of tert-butyl4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate(Example 97)

Step 1.1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (1.5 mL, 19 mmol) was added to1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(95 mg, 0.21 mmol) and the mixture was heated at 80° C. overnight. Themixture was then cooled to rt, concentrated and the residue wasdissolved in toluene and concentrated again to give crude1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneas a TFA salt which was used without further purification. LCMS [M+H]⁺:309.1.

Step 1. tert-butyl4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylatewas prepared from1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneusing the method of Example 1, step 2, wherein1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.Purified by reverse phase HPLC using ACN/Water/0.1% TFA. LCMS [M+H]⁺:428.3. ¹H NMR (500 MHz, Methanol-d4) δ 8.30 (d, J=7.1 Hz, 1H), 7.88 (s,1H), 7.25 (s, 1H), 6.72 (d, J=7.2 Hz, 1H), 3.95 (d, J=13.3 Hz, 2H), 3.78(t, J=6.7 Hz, 2H), 2.79 (t, J=6.8 Hz, 2H), 2.61 (d, J=15.8 Hz, 2H), 2.53(d, J=7.2 Hz, 2H), 1.74 (s, 1H), 1.56 (d, J=13.3 Hz, 2H), 1.34 (s, 9H),1.13-0.98 (m, 2H).

Example 98. Preparation of1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1:3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

HATU (28 mg, 0.073 mmol) and isobutyric acid (6.2 μl, 0.097 mmol) wereadded to a solution of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (25 mg, 0.049 mmol) in DMF (1 mL) at rt. The mixture wasstirred at rt for 5 min and then DIPEA (0.034 mL, 0.19 mmol) was added.The mixture was stirred at rt for 1 h and then diluted with ethylacetate and washed sequentially with water and brine. The organic layerwas dried over sodium sulfate, filtered and concentrated to give crude3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(27 mg, 0.049 mmol). LCMS [M+H]⁺: 548.3.

Step 2:1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 98) was prepared from3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneusing the method of Example 1, step 5, wherein3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyrylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]: 488.3. H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.56 (d,J=7.1 Hz, 1H), 7.99 (s, 1H), 7.37 (d, J=1.7 Hz, 1H), 6.80 (dd, J=7.1,1.9 Hz, 1H), 4.39 (d, J=13.1 Hz, 1H), 3.93 (d, J=13.6 Hz, 1H), 3.77 (t,J=6.7 Hz, 2H), 2.97 (t, J=12.8 Hz, 1H), 2.86 (h, J=6.7 Hz, 1H), 2.79 (t,J=6.7 Hz, 2H), 2.58 (d, J=7.2 Hz, 2H), 2.47 (d, J=12.9 Hz, 1H), 1.86(ddd, J=11.2, 7.5, 3.8 Hz, 1H), 1.73-1.56 (m, 2H), 1.22-1.01 (m, 2H),0.99 (dd, J=12.3, 6.7 Hz, 6H).

The compounds in the following table were prepared by the method ofExample 98, using the appropriate commercially available carboxylic acidin step 1.

Example Mass No. Structure [M + H]⁺ ¹H NMR  99

438.4 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.56 (d, J = 7.1 Hz, 1H), 7.99(s, 1H), 7.37 (d, J = 1.8 Hz, 1H), 6.80 (dd, J = 7.1, 1.9 Hz, 1H), 4.38(d, J = 13.2 Hz, 2H), 3.98-3.87 (m, 2H), 3.77 (t, J = 6.7 Hz, 2H), 2.95(t, J = 12.8 Hz, 1H), 2.79 (t, J = 6.7 Hz, 2H), 2.57 (dd, J = 7.1, 4.1Hz, 2H), 1.85 (ddd, J = 11.1, 7.3, 3.7 Hz, 1H), 1.76-1.52 (m, 7H), 1.30(t, J = 10.4 Hz, 4H), 1.22-0.93 (m, 3H). 100

464.2 (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.55 (dd, J = 7.5, 2.0 Hz,1H), 7.98 (d, J = 2.0 Hz, 1H, 7.36 (s, 1H), 6.79 (dd, J = 7.2, 1.9 Hz,1H), 4.23 (s, 2H), 3.76 (dd, J = 7.8, 5.8 Hz, 2H), 2.78 (dd, J = 7.7,5.8 Hz, 2H), 2.58 (d, J = 6.9 Hz, 2H), 2.55 (d, J = 1.8 Hz, 2H), 1.87(s, 1H), 1.67 (d, J = 13.1 Hz, 2H, 1.38-1.23 (m, 2H), 1.13 (d, J = 19.6Hz, 4H). 101

432.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.62-8.39 (m, 1H), 7.99 (s,1H), 7.48-7.42 (m, 3H, 7.37 (qt, J = 3.0, 1.7 Hz, 3H), 6.80 (dd, J =7.2, 1.9 Hz, 1H), 4.47 (s, 2H), 3.77 (t, J = 6.7 Hz 2H) 3.56 (s, 1H)3.00 (s, 1H), 2.79 (t, J = 6.7 Hz, 3H), 2.60 (s, 2H), 2.03-1.46 (m, 2H),1.19 (s, 2H). 102

460.3 (400 MHz, Methanol-d4) δ 8.40 (d, J = 7.1 Hz, 1H), 7.99 (s, 1H),7.32 (s, 1H), 7.23 (ddd, J = 18.6, 13.0, 7.4 Hz, 5H), 6.80 (d, J = 7.2Hz, 1H), 4.52 (d, J = 13.0 Hz, 1H), 3.87 (q, J = 9.5, 8.1 Hz, 3H),2.97-2.85 (m, 5H), 2.79-2.45 (m, 5H), 1.86 (s, 1H), 1.69 (d, J = 13.4Hz, 1H), 1.58 (d, J = 13.4 Hz, 1H), 1.30 (s, 1H), 1.17-1.00 (m, 1H),0.93-0.76 (m, 1H). NH proton not observed due to solvent exchange. 103

466.2 (400 MHz, Methanol-d4) δ 8.40 (d, J = 7.0 Hz, 1H), 7.98 (s, 1H),7.35 (s, 1H), 6.83 (d, J = 6.9 Hz, 1H), 4.50 (d, J = 13.2 Hz, 1H),3.97-3.81 (m, 3H), 3.04 (t, J = 13.2 Hz, 1H), 2.88 (t, J = 6.6 Hz, 2H),2.70-2.51 (m, 3H), 2.37 (dd, J = 9.5, 6.6 Hz, 2H), 1.93 (ddd, J = 13.5,8.8, 5.1 Hz, 1H), 1.79-1.59 (m, 7H), 1.45 (q, J = 7.4 Hz, 2H), 1.33-1.06(m, 6H), 0.91 (q, J = 13.7, 12.7 Hz, 2H). NH proton not observed due tosolvent exchange.

Example 104. Preparation of1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

DIPEA (0.049 mL, 0.28 mmol) and acetic anhydride (0.016 mL, 0.17 mmol)were added to a solution of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(27 mg, 0.057 mmol) in DCM (1.5 mL) at rt. The mixture was stirred at rtfor 30 min and then partioned between DCM and water. The organic layerseparated, washed with brine, dried over sodium sulfate, filtered andconcentrated to give crude1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dionethat was used without further purification. LCMS [M+H]⁺: 520.4.

Step 2:1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared from1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dioneusing the method of Example 1, step 5, wherein1-(5-((1-acetylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]: 370.3. ¹H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.55 (d,J=7.2 Hz, 1H), 7.98 (s, 1H), 7.35 (d, J=1.6 Hz, 1H), 6.78 (dd, J=7.1,1.8 Hz, 1H), 4.34 (d, J=13.1 Hz, 1H), 3.77 (q, J=6.3 Hz, 3H), 3.03-2.90(m, 1H), 2.78 (t, J=6.7 Hz, 2H), 2.57 (d, J=7.2 Hz, 2H), 2.49-2.41 (m,1H), 1.97 (s, 3H), 1.83 (ddd, J=10.9, 7.4, 3.6 Hz, 1H), 1.61 (t, J=12.6Hz, 2H), 1.08 (dqd, J=47.6, 12.4, 4.2 Hz, 2H).

Example 105. Preparation of1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

2,2-Dimethyloxirane (63 mg, 0.87 mmol) and DIPEA (0.15 mL, 0.87 mmol)were added to a solution of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(150 mg, 0.29 mmol) in THF (2 mL) and MeOH (2 mL) at rt. The mixture washeated at 70° C. overnight, then cooled to rt and concentrated to givecrude3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewhich was used without further purification. LCMS [M+H]⁺: 550.3.

Step 2.3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Trimethyloxonium tetrafluoroborate (40 mg, 0.27 mmol) and DIPEA (0.072mL, 0.41 mmol) were added to a solution of3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(40 mg, 0.068 mmol) in DCM (2 mL) at rt. The mixture was stirred at rtovernight, diluted with DCM and then washed sequentially with saturatedaqueous NaHCO₃ solution and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated to give crude3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewhich was used without further purification. LCMS [M+H]⁺: 564.3.

Step 3:1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared from3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneusing the method of Example 1, step 5, wherein3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-methoxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 414.4. ¹H NMR (500 MHz, Methanol-d4) δ 8.46 (d, J=7.1 Hz,1H), 8.03 (s, 1H), 7.39 (s, 1H), 6.86 (d, J=7.2 Hz, 1H), 3.90 (q, J=6.0Hz, 4H), 3.45 (s, 3H), 3.30-3.12 (m, 4H), 2.90 (t, J=6.8 Hz, 2H), 2.78(d, J=7.3 Hz, 2H), 2.04 (d, J=9.8 Hz, 1H), 1.96-1.77 (m, 4H), 1.46 (s,6H).

Example 106. Preparation of1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(from step 2 of Example 105) by the method of Example 1, step 5, wherein3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 400.4. ¹H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.58 (dd,J=7.2, 2.8 Hz, 1H), 8.00 (s, 1H), 7.36 (d, J=3.2 Hz, 1H), 6.78 (dd,J=7.2, 1.8 Hz, 1H), 4.00-3.62 (m, 2H), 3.57 (d, J=12.8 Hz, 2H),3.30-3.10 (m, 3H), 3.07-2.89 (m, 3H), 2.79 (t, J=6.6 Hz, 2H), 2.63 (dd,J=28.7, 7.0 Hz, 1H), 1.91 (d, J=53.7 Hz, 1H), 1.68 (dt, J=42.6, 14.6 Hz,4H), 1.23 (d, J=5.3 Hz, 6H).

Example 107. Preparation of1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To a stirred solution of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(250 mg, 0.523 mmol) in acetonitrile (5.0 mL) was added lithiumperchlorate (110 mg, 1.046 mmol). The reaction was stirred for 10 minfollowed by the addition of 1-oxaspiro[2.5]octane (293 mg, 2.61 mmol).The mixture was stirred at 90° C. for 4 h. After cooling to rt, thereaction was diluted with EtOAc and water. The organic layer was driedover Na₂SO₄, filtered and concentrated to give crude3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(200 mg, crude). LCMS [M+H]⁺: 590.3.

Step 2.3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To a stirred solution of3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(80 mg, 0.135 mmol) in DCM (10 mL) at 0° C. was added DAST (43 mg, 0.271mmol). The reaction was stirred at 0° C. for 1 h. The reaction was thendiluted with DCM and water. The organic layer was dried over Na₂SO₄,filtered and concentrated to give crude3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(50 mg, crude). LCMS [M+H]⁺: 592.2.

Step 3:1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 107) was prepared from3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(10 mg, 0.016 mmol) using the method of Example 1, step 5, wherein3-(2,4-dimethoxybenzyl)-1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.The crude compound was purified by chiral HPLC: COLUMN: CHIRALPAK IG,250 mm×20 mm×5 μm, MOBILE PHASE: HEXANE (A), 0.1% DEA in MeOH: EtOH, 1:1(B), FLOW: 15 mL ISOCRATIC: 75(A):25(B). The collected fractions wereconcentrated to afford1-(5-((1-((1-fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(3 mg, 0.006 mmol, 33% yield) as an off-white solid. LCMS [M+H]⁺: 442.3.HPLC Rt=4.95 min. ¹H NMR (300 MHz, Methanol-d4) δ 8.40 (d, J=7.1 Hz,1H), 7.98 (s, 1H), 7.34 (s, 1H), 6.81 (d, J=7.2 Hz, 1H), 3.88 (t, J=6.6Hz, 2H), 2.98-2.84 (m, 4H), 2.61 (d, J=6.5 Hz, 2H), 2.42 (d, J=23.5 Hz,2H), 2.07 (t, J=11.2 Hz, 2H), 1.82 (s, 2H), 1.69-1.47 (m, 10H),1.43-1.24 (m, 3H). NH proton not observed due to solvent exchange.

Example 108. Preparation of1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (25 mL, 5.28 mmol) was added to tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate(3.05 g, 5.28 mmol). The mixture was heated overnight at in a sealedvial at 85° C. The mixture was then cooled to rt and, concentrated andazeotropically dried with toluene to provide crude product (2.33 g, 5.28mmol). A portion (˜20 mg) of the crude material was dissolved in DMSO,filtered through a 1 micron filter and purified by reverse phase HPLCusing ACN/Water/0.1% TFA. The fractions containing the product werecombined, frozen and lyophilized to afford a TFA salt of1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 108) (8 mg, 0.018 mmol). LCMS [M+H]⁺: 328.3. ¹H NMR (500 MHz,DMSO-d6) δ 10.44 (s, 1H), 8.59 (d, J=7.1 Hz, 1H), 8.52 (d, J=11.4 Hz,1H), 8.23 (d, J=11.4 Hz, 1H), 8.01 (s, 1H), 7.39 (d, J=1.8 Hz, 1H), 6.80(dd, J=7.2, 1.9 Hz, 1H), 3.77 (t, J=6.7 Hz, 2H), 3.26 (d, J=12.6 Hz,2H), 2.90-2.76 (m, 4H), 2.61 (d, J=7.0 Hz, 2H), 1.89 (ddh, J=14.7, 7.3,3.6 Hz, 1H), 1.80-1.72 (m, 2H), 1.35 (tdd, J=14.3, 12.0, 4.0 Hz, 2H).

Example 109. Preparation of1-(5-((1-isobutylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Isobutyraldehyde (1.90 g, 26.4 mmol) and triethylamine (1.10 mL, 7.92mmol) were added to a solution of1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate (Example 108) (2.33 g, 5.28 mmol) in DCM (30 mL) andMeOH (2 mL). The reaction mixture was stirred at rt for 30 min and thensodium triacetoxyborohydride (5.59 g, 26.4 mmol) was added. The reactionmixture was stirred overnight at rt and then quenched with a solution ofsaturated aqueous NaHCO₃ and extracted three times with DCM. Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated. Silica gel column chromatography (eluted with0-100% EtOAc/EtOH (3:1), heptane and 0.1% TEA) provided a light brownsolid which was triturated with diethyl ether to give1-(5-((1-isobutylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneas an off white solid. (1055 mg, 2.738 mmol, 52% yield). LCMS [M+H]⁺:384.3. ¹H NMR (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.53 (d, J=7.1 Hz,1H), 7.97 (d, J=1.4 Hz, 1H), 7.34 (s, 1H), 6.83-6.63 (m, 1H), 3.76 (t,J=6.6 Hz, 2H), 2.78 (t, J=6.8 Hz, 4H), 2.55 (d, J=6.5 Hz, 2H), 1.97 (d,J=7.4 Hz, 2H), 1.75 (dt, J=19.4, 9.2 Hz, 3H), 1.56 (d, J=11.5 Hz, 3H),1.31-1.09 (m, 2H), 0.83 (d, J=6.5 Hz, 6H).

The compounds in the following table were prepared by the method ofExample 109, using the appropriate commercially available aldehyde.

Example Mass No. Structure [M + H]⁺ ¹H NMR 110

398.4 (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.69-8.52 (m, 1H), 8.00 (d, J= 1.6 Hz, 1H), 7.36 (s, 1H), 6.78 (dd, J = 7.2, 1.8 Hz, 1H), 3.77 (dd, J= 7.5, 6.1 Hz, 2H), 3.47 (d, J = 12.3 Hz, 1H), 3.17 (s, 1H, 3.10-2.99(m, 2H), 2.94 (d, J = 4.0 Hz, 2H), 2.79 (dd, J = 7.5, 6.0 Hz, 2H), 2.67(d, J = 7.1 Hz, 1H, 2.61 (d, J = 6.5 Hz, 2H), 1.92 (d, J = 55.2 Hz, 1H),1.81-1.48 (m, 4H), 1.03 (d, J = 1.3 Hz, 9H). 111

419.4 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.68 (dd, J = 4.9, 1.7 Hz,1H), 8.58 (d, J = 7.1 Hz, 1H, 8.00 (s, 1H), 7.93 (td, J = 7.7, 1.8 Hz,1H), 7.59-7.44 (m, 2H), 7.37 (s, 1H), 6.79 (dd, J = 7.2, 1.9 Hz, 1H),4.45 (s, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.40 (d, J = 13.0 Hz, 2H), 3.03(t, J = 12.5 Hz, 2H), 2.78 (t, J = 6.7 Hz, 2H), 2.62 (d, J = 6.9 Hz,2H), 2.00-1.73 (m, 3H), 1.64-1.44 (m, 2H).

Example 112. Preparation of1-(5-((1-(2-cyclohexyl-2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.1-(5-((1-(2-cyclohexyl-2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

To a solution of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(200 mg, 0.419 mmol) and 2-cyclohexyl-2,2-difluoroacetaldehyde (1.36 g,8.38 mmol) [see Org. Lett. 2009, 11, 943-946] in DCE (2 mL) was addedNaBH(OAc)₃ (133 mg, 0.628 mmol) at rt, then the mixture was stirred for16 h. The reaction mixture was diluted with water and then extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by prep-HPLC (column: Waters Xbridge C18 150×25 mm×10 μm;mobile phase: [water (0.225% FA)-ACN]; B %: 24%-54%, 10 min), the eluentwas concentrated to remove MeCN and lyophilized to give1-(5-((1-(2-cyclohexyl-2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(100 mg, 0.16 mmol, 38% yield) as a yellow solid. LCMS [M+H]⁺: 624.6.

Step 2:1-(5-((1-(2-cyclohexyl-2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 1112) was prepared from1-(5-((1-(2-cyclohexyl-2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dioneusing the method of Example 1, step 5, wherein1-(5-((1-(2-cyclohexyl-2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 474.3. ¹H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.53 (d,J=6.8 Hz, 1H), 7.97 (s, 1H), 7.34 (s, 1H), 6.77-6.75 (m, 1H), 3.76-3.73(m, 2H), 2.85-2.82 (m, 2H), 2.78-2.75 (m, 2H), 2.70-2.59 (m, 2H),2.55-2.52 (m, 2H), 2.08-2.07 (m, 2H), 1.99-1.85 (m, 1H), 1.85-1.67 (m,4H), 1.64-1.61 (m, 1H), 1.55-1.52 (m, 3H), 1.27-1.05 (m, 7H).

The compounds in the following table were prepared by the method ofExample 112, using the appropriate commercially available aldehyde andTEA or DIPEA (2 equiv) in step 1.

Example Mass No. Structure [M + H]⁺ ¹H NMR 113

454.3 (300 MHz, Methanol-d4) 8.39 (d, J = 7.2 Hz, 1H), 8.31 (s, 1H),7.96 (s, 1H), 7.34 (s, 1H), 6.79 (d, J = 7.2 Hz, 1H), 3.84 (t, J = 6.8Hz, 2H), 3.68-3.38 (m, 4H), 3.33-3.19 (m, 1H), 2.98-2.79 (m, 5H), 2.65(d, J = 6.7 Hz, 2H), 2.47-2.03 (m, 1H), 2.02-1.81 (m, 3H), 1.77-1.33 (m,5H), 1.14 (d, J = 6.4 Hz, 3H), 1.09 (d, J = 6.0 Hz, 2H), 0.86 (q, J =11.8 Hz, 1H). NH protons not observed due to solvent exchange 114

422.2 (400 MHz, CD₃OD): δ 8.44 (d, J = 7.2 Hz, 1H), 8.02 (s, 1H), 7.56(s, 1H), 7.36 (s, 1H), 6.83 (d, J = 6.8 Hz, 1H), 6.56 (s, 1H), 4.47 (s,2H), 3.95 (s, 3H), 3.89 (t, J = 6.8 Hz, 2H), 3.57-3.54 (m, 2H), 3.05 (m,2H), 2.89 (t, J = 7.2 Hz, 2H), 2.71-2.69 (m, 2H), 2.01-1.97 (m, 3H),1.53 (m, 2H) ppm. NH proton not observed due to solvent exchange 115

425.0 (400 MHz, Methanol-d4) δ 9.09 (d, J = 2.0 Hz, 1H), 8.42 (d, J =7.1 Hz, 1H), 8.36 (s, 1H), 8.00 (s, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.36(s, 1H), 6.82 (dd, J = 7.6, 1.6 Hz, 1H), 4.38 (s, 2H), 3.88 (t, J = 6.8Hz, 2H), 3.45 (d, J = 12.5 Hz, 2H), 2.98-2.85 (m, 4H), 2.69 (d, J = 6.7Hz, 2H), 1.91 (d, J = 15.0 Hz, 3H), 1.54 (q, J = 13.1 Hz, 2H). NHprotons not observed due to solvent exchange 116

422.2 (400 MHz, Methanol-d4) δ 9.04 (s, 1H), 8.43 (d, J = 6.9 Hz, 1H),8.06-8.01 (m, 1H), 7.83 (s, 1H), 7.39 (d, J = 6.5 Hz, 1H), 6.88-6.80 (m,1H), 4.47 (s, 2H), 3.97 (s, 3H), 3.88 (t, J = 6.8 Hz, 2H), 3.56 (d, J =11.9 Hz, 2H), 3.06 (t, J = 12.8 Hz, 2H), 2.89 (t, J = 6.8 Hz, 3H), 2.70(d, J = 6.7 Hz, 2H). NH proton not observed due to solvent exchange. 117

476.3 (400 MHz, CD₃OD) δ 8.42.8.40 (m, 2H), 7.98 (s, 1H), 7.34 (s, 1H),6.07 (d, J = 6.8 Hz, 1H), 3.86 (t, J = 7.2 Hz, 2H), 3.48.3.38 (brs, 2H),3.15 (s, 2H), 2.88-2.84 (m, 4H), 2.69 (d, J = 6.8 Hz, 2H), 2.01-1.65 (s,1H). Two protons not integrated due to peak broadening. NH proton notobserved due to solvent exchange.

Example 118. Preparation of1-(5-((1-((3-methyloxetan-3-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 108) using the method of Example 1, step 4, wherein3-(bromomethyl)-3-methyloxetane was used in place of(bromomethyl)cyclohexane. LCMS [M+H]⁺: 412.3. ¹H NMR (400 MHz, DMSO-d6)δ 10.42 (s, 1H), 8.70-8.39 (m, 1H), 8.00 (d, J=1.9 Hz, 1H), 7.37 (s,1H), 6.78 (dd, J=7.2, 2.0 Hz, 1H), 4.45 (d, J=6.2 Hz, 2H), 4.24-4.20 (m,2H), 3.82-3.67 (m, 3H), 3.60-3.31 (m, 3H), 3.22 (d, J=12.2 Hz, 2H),3.15-2.88 (m, 2H), 2.78 (t, J=6.8 Hz, 2H), 2.60 (d, J=6.4 Hz, 1H), 1.78(d, J=14.6 Hz, 3H), 1.70-1.38 (m, 4H).

Example 119. Preparation of1-(5-((1-(oxetan-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 108) using the method of Example 1, step 4, wherein3-(bromomethyl)oxetane was used in place of (bromomethyl)cyclohexane.LCMS [M+H]⁺: 398.4. ¹H NMR (500 MHz, Methanol-d4) δ 8.45 (d, J=7.2 Hz,1H), 8.03 (d, J=1.8 Hz, 1H), 7.38 (s, 1H), 6.84 (d, J=7.2 Hz, 1H), 4.84(d, J=7.1 Hz, 2H), 4.50 (t, J=6.0 Hz, 1H), 3.90 (t, J=6.7 Hz, 2H),3.77-3.67 (m, 1H), 3.67-3.42 (m, 4H), 3.29-3.23 (m, 1H), 3.04-2.88 (m,4H), 2.77-2.65 (m, 2H), 2.12-1.92 (m, 3H), 1.53 (t, J=14.3 Hz, 2H).

Example 120. Preparation of1-(5-((1-(2-(1H-imidazol-4-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 108) using the method of Example 1, step 4, wherein4-(2-chloroethyl)-1H-imidazole was used in place of(bromomethyl)cyclohexane and with the addition of KI (1.5 equiv). LCMS[M+H]⁺: 422.4. ¹H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 9.73-9.28 (m,1H), 9.02 (s, 1H), 8.59 (d, J=7.1 Hz, 1H), 8.00 (s, 1H), 7.53 (s, 1H),7.37 (s, 1H), 6.79 (dd, J=7.1, 1.9 Hz, 1H), 3.76 (t, J=6.7 Hz, 2H),3.56-3.43 (m, 2H), 3.39-3.29 (m, 2H), 3.10 (t, J=7.9 Hz, 2H), 3.02-2.87(m, 2H), 2.78 (t, J=6.7 Hz, 2H), 2.65-2.56 (m, 2H), 1.96-1.77 (m, 3H),1.52-1.38 (m, 2H).

Example 121. Preparation of1-(5-((1-(3-hydroxy-2-(hydroxymethyl)propyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(5-((1-(oxetan-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 119) using the method of Example 1, step 5, wherein1-(5-((1-(oxetan-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 416.3. ¹H NMR (500 MHz, Methanol-d4) δ 8.45 (d, J=7.2 Hz,1H), 8.03 (d, J=1.6 Hz, 1H), 7.40 (d, J=11.5 Hz, 1H), 6.86 (dd, J=9.2,7.1 Hz, 1H), 5.51 (d, J=1.5 Hz, 1H), 3.91 (t, J=6.6 Hz, 2H), 3.77-3.67(m, 4H), 3.58 (dd, J=10.7, 7.6 Hz, 2H), 3.43-3.36 (m, 1H), 3.25 (d,J=6.8 Hz, 2H), 3.02-2.88 (m, 4H), 2.72 (d, J=6.8 Hz, 2H), 2.32 (s, 1H),2.02 (t, J=18.4 Hz, 3H), 1.55 (q, J=13.2 Hz, 2H).

Example 122. Preparation of1-(5-((1-(2-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

DIPEA (0.053 mL, 0.31 mmol) and 1-(chloromethyl)-2-methoxybenzene (11mg, 0.073 mmol) were added to a solution of1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 108) (20 mg, 0.061 mmol) in DCM. The mixture was stirred at rtfor 30 min. Additional 1-(chloromethyl)-2-methoxybenzene (11 mg, 0.073mmol) and DIPEA (0.053 mL, 0.31 mmol) were added and the mixture wasstirred for 2 h at rt. The reaction was then diluted with DCM and washedsequentially with water and brine. The organic layer was dried oversodium sulfate, filtered and concentrated. The residue was dissolved inDMSO, filtered through a 1 micron filter and purified by reverse phaseHPLC using ACN/water/0.1% TFA. The fractions containing the product werecombined, frozen and lyophilized to afford a TFA salt of1-(5-((1-(2-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(2.3 mg, 0.0039 mmol, 6% yield). LCMS [M+H]⁺: 448.2. ¹H NMR (500 MHz,DMSO-d6) δ 10.45 (d, J=14.6 Hz, 1H), 8.60 (dd, J=12.9, 7.2 Hz, 1H), 8.01(d, J=8.5 Hz, 1H), 7.54-7.42 (m, 2H), 7.42-7.33 (m, 1H), 7.14 (d, J=8.3Hz, 1H), 7.05 (q, J=7.8 Hz, 1H), 6.78 (dd, J=7.2, 1.9 Hz, 1H), 4.22 (d,J=4.9 Hz, 2H), 3.84 (s, 3H), 3.77 (t, J=6.7 Hz, 2H), 3.36 (d, J=12.1 Hz,2H), 2.95 (d, J=11.6 Hz, 2H), 2.78 (t, J=6.8 Hz, 2H), 2.59 (d, J=6.7 Hz,2H), 1.95-1.70 (m, 3H), 1.44 (q, J=12.2, 11.0 Hz, 2H).

Example 123. Preparation of1-(5-((1-(cyclohexylmethyl)-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoropiperidine-1-carboxylate

To an oven-dried vial was added tert-butyl4-(bromomethyl)-4-fluoropiperidine-1-carboxylate (0.308 g, 1.04 mmol),1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(0.367 g, 0.8 mmol), NiCl₂(DME) (8.8 mg, 0.040 mmol),pyridine-2,6-bis(carboximidamide) dihydrochloride (9.4 mg, 0.040 mmol),NaI (0.030 g, 0.20 mmol) and Zn (0.105 g, 1.60 mmol). The vial wassealed with a septum cap, evacuated and refilled with nitrogen 3 times.DMA (2.7 mL) and TFA (6 μl, 0.08 mmol) were added and the reaction wasstirred at rt for 2 mm. The vial was carefully evacuated and refilledwith nitrogen 3 times to remove any H₂. The reaction was then heatedovernight at 70° C., forming a brown reaction mixture. The reaction wascooled to rt, diluted with EtOAc and filtered through a plug of silicagel, eluting with EtOAc. The eluent was concentrated and the residue waspurified by silica gel column chromatography (eluted with 0-100% EtOAcin heptane) to give tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydro pyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoropiperidine-1-carboxylate(0.47 g, 0.80 mmol, 98% yield, purity 70%). LCMS [M+H]⁺: 596.4. Theproduct was used without further purification.

Step 2:1-(5-((1-(cyclohexylmethyl)-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared from tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoropiperidine-1-carboxylateusing the method of Example 109, wherein cyclohexanecarbaldehyde wasused in place of isobutyraldehyde. LCMS [M+H]⁺: 442.2. ¹H NMR (400 MHz,DMSO-d6) δ 10.44 (s, 1H), 8.62 (dd, J=7.1, 0.9 Hz, 1H), 8.04 (d, J=1.9Hz, 1H), 7.43 (d, J=30.9 Hz, 1H), 6.92-6.71 (m, 1H), 3.81-3.74 (m, 2H),3.43 (d, J=12.2 Hz, 2H), 3.28-2.86 (m, 6H), 2.82-2.73 (m, 2H), 2.14-1.84(m, 4H), 1.82-1.53 (m, 6H), 1.18 (dt, J=30.0, 12.3 Hz, 3H), 1.01-0.84(m, 2H).

Example 124. Preparation of1-(5-((4-fluoro-1-isobutylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 123, wherein isobutyraldehyde wasused in place of cyclohexanecarbaldehyde. LCMS [M+H]⁺: 402.4. ¹H NMR(400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.62 (d, J=7.0 Hz, 1H), 8.04 (d,J=1.9 Hz, 1H), 7.47 (s, 1H), 6.82 (d, J=7.3 Hz, 1H), 3.78 (t, J=6.8 Hz,2H), 3.44 (d, J=12.5 Hz, 2H), 3.15-2.89 (m, 6H), 2.83-2.73 (m, 2H),2.17-1.87 (m, 5H), 0.93 (dd, J=6.7, 2.0 Hz, 6H).

Example 125. Preparation of1-(5-((1-(cyclobutylmethyl)-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 123, whereincyclobutanecarbaldehyde was used in place of cyclohexanecarbaldehyde.LCMS [M+H]⁺: 402.4. ¹H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.61 (dd,J=7.2, 1.0 Hz, 1H), 8.04 (s, 1H), 7.46 (d, J=1.6 Hz, 1H), 6.93-6.73 (m,1H), 3.78 (t, J=6.7 Hz, 2H), 3.34 (d, J=12.3 Hz, 2H), 3.23-2.93 (m, 6H),2.79 (t, J=6.8 Hz, 2H), 2.67 (p, J=7.3, 6.9 Hz, 1H), 2.15-1.92 (m, 5H),1.91-1.71 (m, 5H).

Example 126. Preparation of1-(5-((1-benzyl-4-fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoropiperidine-1-carboxylateusing the method of Example 1, steps 3 to 5, wherein benzyl bromide wasused in place of (bromomethyl)cyclohexane. LCMS [M+H]⁺: 436.2. ¹H NMR(500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.61 (d, J=7.1 Hz, 1H), 8.03 (s,1H), 7.46 (d, J=16.6 Hz, 6H), 6.80 (d, J=7.3 Hz, 1H), 4.34 (d, J=5.1 Hz,2H), 3.77 (t, J=6.6 Hz, 2H), 3.21-3.01 (m, 6H), 2.77 (t, J=6.7 Hz, 2H),2.64 (s, 1H), 2.07-1.80 (m, 3H).

Example 127. Preparation of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. 1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-ium2,4-dinitrophenolate

tert-Butyl (3-methylpyridin-4-yl)carbamate (2.447 g, 10.0 mmol) andO-(2,4-dinitrophenyl)hydroxylamine (2.19 g, 11.0 mmol) were added to areaction flask. 2-MeTHF (20 mL) was added and the reaction was heated toat 40° C. for 1 h, then stirred at rt overnight. AdditionalO-(2,4-dinitrophenyl)hydroxylamine (600 mg, 3.00 mmol, 0.3 eq) was addedand the reaction stirred for another 2 h at 40° C. The reaction wasdiluted with isopropanol and concentrated to give a yellow solid whichwas suspended in cold IPA, filtered and dried to give1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-ium2,4-dinitrophenolate (5.5 g, crude) which was used without furtherpurification. LCMS [M]⁺: 224.1.

Step 2. ethyl5-((tert-butoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate

Potassium carbonate (5.60 g, 40.5 mmol) was added to a mixture of1-amino-4-((tert-butoxycarbonyl)amino)-3-methylpyridin-1-ium2,4-dinitrophenolate (5.5 g, 13.5 mmol) in DMF (13.5 mL) at 0° C. After5 min, ethyl propiolate (1.50 mL, 14.8 mmol) was added and the reactionwas stirred at 0° C. and allowed to warm to rt overnight. Tworegioisomers were present by LCMS. The reaction was concentrated and theresidue was suspended in water, filtered and the solid was purified bysilica gel chromatography to give ethyl5-((tert-butoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate(849 mg, 2.66 mmol, 20% yield) as a single regioisomer. LCMS [M+H]⁺:320. ¹H NMR (500 MHz, CDCl₃) δ 8.37 (d, J=1.8 Hz, 1H), 8.34 (d, J=7.6Hz, 1H), 7.80 (d, J=7.6 Hz, 1H), 6.58 (s, 1H), 4.37-4.27 (m, 2H), 2.77(d, J=1.8 Hz, 3H), 1.55 (d, J=1.7 Hz, 9H), 1.39 (td, J=7.1, 1.8 Hz, 3H).

Step 3. ethyl 5-amino-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate

TFA (3.3 mL) was added to a solution of ethyl5-((tert-butoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate(850 mg, 2.66 mmol) in DCM (10 mL) at rt. The reaction was stirred at rtfor 1 h and then concentrated. The residue was azeotropically dried withtoluene to give ethyl5-amino-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (850 mg, 2.66mmol) as a light yellow solid. LCMS [M+H]⁺: 220.

Step 4. ethyl 5-iodo-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate

A solution of sodium nitrite (37.9 mg, 0.550 mmol) in water (0.50 mL)was added dropwise to a suspension of ethyl5-amino-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (167 mg, 0.5 mmol)in MeCN (0.83 mL) and aqueous 6 M HCl (2.5 mL) at 0° C. The reactionturned bright yellow and was stirred at 0° C. for 1 h. A solution ofpotassium iodide (166 mg, 1.00 mmol) in water (0.50 mL) was addeddropwise to the vigorously stirring reaction; the reaction turned darkbrown and bubbled and a precipitate formed. After 15 min, the reactionwas diluted with water, filtered and the solid was washed with water.The solid was then dissolved in EtOH/DCM and concentrated. The solid wassuspended in cold methanol, filtered and dried to give ethyl5-iodo-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate (141 mg, 0.427mmol, 85% yield) as a light yellow solid. LCMS [M+H]⁺: 331.

Step 5. ethyl5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate

Prepared from ethyl 5-iodo-4-methylpyrazolo[1,5-a]pyridine-3-carboxylateby the method of Example 1, step 2, wherein ethyl5-iodo-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate was used in placeof1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H-tBu]⁺: 346.1.

Step 6.5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylicacid

Sodium hydroxide (360 mg, 9.00 mmol) was added to a solution of ethyl5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylate(723 mg, 1.80 mmol) in EtOH (7.2 mL) and water (1.8 mL). The mixture washeated at 60° C. for 3 h, then cooled to rt and concentrated. Theresidue was dissolved in water, filtered and then aqueous 6 M HCl wasadded dropwise until the product precipitated. The supernatant wasdecanted and the solid was washed with water, dried and purified bysilica gel chromatography (eluted with 0-50% of (1% AcOH in 3:1EtOAc/EtOH) in heptane) to give5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylicacid (636 mg, 1.703 mmol, 95% yield) as an off-white solid. LCMS[M+H-tBu]⁺: 318.

Step 7. tert-butyl4-((3-((ethoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate

DIPEA (675 μl, 3.86 mmol) was added to a solution of5-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridine-3-carboxylicacid (481 mg, 1.29 mmol) in dioxane (4.3 mL) at rt. The bright yellowmixture was stirred at rt for 3 h, then EtOH (1.5 mL, 25.8 mmol) wasadded and the reaction was heated at 100° C. for 15 min. The reactionwas cooled to rt, diluted with water and brine and extracted with EtOAc.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by silica gel chromatography (eluted with 0-60%EtOAc/heptane) to give tert-butyl4-((3-((ethoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate(479 mg, 1.150 mmol, 89% yield) as a colorless oil. LCMS [M+H-tBu]⁺:361.

Step 8. tert-butyl4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate

Acrylamide (14.2 mg, 0.200 mmol) and tert-butyl4-((3-((ethoxycarbonyl)amino)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate(41.7 mg, 0.1 mmol) were added to a vial followed by tBuOH (0.5 mL) andpotassium tert-butoxide (110 μl, 0.110 mmol) (1.0 M in THF)—the reactionturned light yellow. The mixture was heated at 60° C. overnight. Thereaction was quenched with saturated aqueous NaHCO₃ and water. Themixture was extracted with EtOAC, dried over Na₂SO₄, filtered andconcentrated to give crude tert-butyl4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate(39 mg, 0.088 mmol, 88% yield). LCMS [M+H-Boc]⁺: 342.

Step 9.1-(4-methyl-5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (215 μl) was added to a solution of tert-butyl4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methylpyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-carboxylate(38 mg, 0.086 mmol) in DCM (645 μl) at rt. The reaction was stirred atrt for 30 min and was then concentrated to give crude1-(4-methyl-5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionethat was used without further purification. LCMS [M+H]: 342.

Step 10.1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]8pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(4-methyl-5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneby the method of Example 109, wherein cyclohexanecarbaldehyde was usedin place of isobutyraldehyde. LCMS [M+H]⁺: 438.5. ¹H NMR (500 MHz,DMSO-d6) j 10.45 (s, 1H), 8.60 (s, 1H), 8.44 (d, J=7.1 Hz, 1H), 7.98 (m,1H), 6.73 (d, J=7.1 Hz, 1H), 3.79 (dt, J=13.3, 7.1 Hz, 1H), 3.65 (dt,J=12.6, 6.4 Hz, 2H), 2.88-2.80 (m, 3H), 2.76 (t, J=6.8 Hz, 2H),2.68-2.59 (m, 2H), 2.35 (m, 3H), 1.86-1.58 (m, 10H), 1.53 (d, J=12.6 Hz,2H), 1.33-1.07 (m, 4H), 0.92 (d, J=12.8 Hz, 2H).

The compounds in the following table were prepared by the method ofExample 1, using tert-butyl 3-methylenepyrrolidine-1-carboxylate in step2 and the appropriate commercially available halide in step 4.

Example Mass No. Structure [M + H]⁺ ¹H NMR 128

410.3 (500 MHz, Methanol-d4) δ 8.35 (d, J = 7.2 Hz, 1H), 7.93 (s, 1H),7.30 (d, J = 6.9 Hz, 1H, 6.75 (d, J = 7.2 Hz, 1H), 3.80 (t, J = 6.5 Hz,2H), 3.73-3.42 (m, 2H), 2.95 (t, J = 7.2 Hz, 2H), 2.87-2.71 (m, 5H),2.70-2.58 (m, 1H), 2.21-2.02 (m, 1H), 1.84 (q, J = 10.8, 9.0 Hz, 1H),1.65 (dd, J = 35.6,13.5 Hz, 6H), 1.19 (ddd, J = 41.2, 25.5, 12.9 Hz,4H), 0.93 (d, J = 12.3 Hz, 2H). 129

405.3 (500 MHz, DMSO-d6) δ 10.45 (d, J = 3.2 Hz, 1H), 8.73 (dd, J = 6.0,2.1 Hz, 1H), 8.66 (d, J = 5.5 Hz, 1H), 8.60 (d, J = 7.2 Hz, 1H), 8.02(d, J = 5.0 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.61-7.48 (m, 1H), 7.39(d, J = 23.9 Hz, 1H), 6.81 (td, J = 5.1, 2.6 Hz, 1H), 4.45 (t, J = 5.1Hz, 2H), 3.77 (q, J = 6.0 Hz, 2H), 3.58-3.25 (m, 3H), 3.16 (dd, J =11.6, 6.1 Hz, 1H), 3.02-2.55 (m, 5H), 2.25-1.94 (m, 1H), 1.91-1.55 (m,1H). 130

382.3 (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.60 (d, J = 7.1 Hz, 1H), 8.02(s, 1H), 7.39 (d, J = 16.8 Hz, 1H), 6.82 (ddd, J = 6.5, 4.2, 1.7 Hz,1H), 3.83-3.72 (m, 2H), 3.50 (dq, J = 14.3, 6.4 Hz, 2H), 3.19 (q, J =7.0 Hz, 3H), 3.15-2.95 (m, 1H), 2.85-2.69 (m, 5H), 2.60 (tt, J = 19.8,9.2 Hz, 1H), 2.18-1.95 (m, 3H), 1.89 (ddt, J = 12.3, 8.4, 3.6 Hz, 1H),1.83-1.71 (m, 4H). 131

422.3 (500 MHz, Methanol-d4) δ 8.34 (d, J = 7.1 Hz, 1H), 7.92 (s, 1H,7.41 (q, J = 7.3 Hz, 1H, 7.30 (s, 1H), 7.21 (dd, J = 14.6, 8.6 Hz, 2H),7.14 (t, J = 8.7 Hz, 1H), 6.74 (d, J = 7.2 Hz, 1H), 4.31 (s, 2H), 3.79(t, J = 6.7 Hz, 2H), 3.45 (d, J = 26.2 Hz, 2H), 3.07 (s, 1H), 2.88 (t, J= 10.8 Hz, 1H), 2.79 (t, J = 6.7 Hz, 4H), 2.63 (s, 1H), 2.13 (d, J =61.3 Hz, 1H), 1.93-1.56 (m, 1H). 132

370.3 (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.61 (d, J = 7.2 Hz, 1H), 8.02(s, 1H), 7.39 (d, J = 13.4 Hz, 1H), 6.82 (ddd, J = 7.2, 3.7, 1.9 Hz,1H), 3.78 (t, J = 6.7 Hz, 2H), 3.50 (m, 1H), 3.30-3.13 (m, 2H), 3.00(dt, J = 9.8, 6.6 Hz, 2H), 2.88-2.71 (m, 5H), 2.61 (dd, J = 18.5, 9.7Hz, 1H), 2.19-1.88 (m, 2H), 1.86-1.55 (m, 1H), 0.95 (dd, J = 6.6, 4.1Hz, 6H).

Example 133. Preparation of1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 1, steps 2 and 5, whereintert-butyl 3-methyleneazetidine-1-carboxylate was used in place oftert-butyl 4-methylenepiperidine-1-carboxylate. LCMS [M+H]⁺: 300.0. ¹HNMR (300 MHz, CD₃OD) δ 8.53 (s, 1H), 8.44 (d, J=7.2 Hz, 1H), 8.01 (s,1H), 7.37 (s, 1H), 6.82-6.79 (m, 1H), 4.09 (t, J=8.7 Hz, 2H), 3.92-3.86(m, 4H), 3.34 (m, 1H), 3.03 (d, J=8.1 Hz, 2H), 2.88 (t, J=7.2 Hz, 2H).

Example 134. Preparation of1-(5-((1-isobutylazetidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 133) using the method of Example 109, wherein1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate. LCMS [M+H]⁺: 356.3. ¹H NMR (300 MHz, CD₃OD) δ 8.55 (s,1H), 8.43 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.37 (s, 1H), 6.81-6.79 (m,1H), 3.96-3.87 (m, 4H), 3.63-3.61 (m, 2H), 3.13-3.09 (m, 1H), 3.00 (d,J=8.0 HZ, 2H), 2.89 (d, J=7.2 Hz, 2H), 2.79 (d, J=6.8 Hz, 2H), 1.84-1.81(m, 1H), 0.96 (d, J=6.8 Hz, 6H), NH proton not observed due to solventexchange.

Example 135. Preparation of1-(5-((1-(cyclohexylmethyl)azetidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 133) using the method of Example 109, wherein1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate and cyclohexanecarbaldehyde was used in place ofisobutyraldehyde. LCMS [M+H]⁺: 396.1. ¹H NMR (300 MHz, CD₃OD) δ 8.54 (s,1H), 8.42 (d, J=7.2 Hz, 1H), 8.00 (s, 1H), 7.35 (s, 1H), 6.80-6.77 (m,1H), 3.95-3.86 (m, 4H), 3.62-3.56 (m, 2H), 3.09-3.07 (m, 1H), 2.99-2.97(m, 2H), 2.88 (d, J=6.6 Hz, 2H), 2.80-2.78 (m, 2H), 1.73-1.70 (m, 5H),1.51 (s, 1H), 1.30-0.95 (m, 5H).

Example 136. Preparation of1-(5-((1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. (4-methylenepiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone

To a stirred solution of tetrahydro-2H-pyran-4-carboxylic acid (4.0 g,27.7 mmol) in THF (80 mL) was added HATU (15.81 g, 41.60 mmol), DIPEA(14.2 mL, 83.2 mmol) at 0° C. The mixture was stirred for 10 minfollowed by the addition of a solution of 4-methylenepiperidine (4.41 g,33.3 mmol) in THF (20 mL). The reaction mixture was then stirred at rtfor 12 h. The reaction was then quenched with water and extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude material was purified by silica gelchromotography (eluting with 50% EtOAc in hexanes) to afford(4-methylenepiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (3.8 g,18.1 mmol, 59% yield). LCMS [M+H]⁺: 210.0.

Step 2.4-methylene-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine

To a stirred solution of(4-methylenepiperidin-1-yl)(tetrahydro-2H-pyran-4-yl)methanone (1.0 g,4.7 mmol) in THF (12 mL) was added ZrCl₄ (1.09 g, 4.7 mmol) at −20° C.and the mixture was stirred for 30 min. A solution of MeMgBr.Et₂O (9.4mL, 28.2 mmol, 3.0 M) was added and the mixture was stirred for 10 minat −20° C. and then at rt for 2 h. After completion, the reaction wasquenched with water (10 mL) and extracted with EtOAc. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified by silica gel chromotography (eluting with50% EtOAc in hexanes) to afford4-methylene-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine (250mg, 1.12 mmol, 24% yield). LCMS [M+H]⁺: 224.0.

Step 3:1-(5-((1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared from4-methylene-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine usingthe method of Example 1, steps 2 and 5, wherein was used in place of4-methylene-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidine wasused in place of tert-butyl 4-methylenepiperidine-1-carboxylate. LCMS[M+H]⁺: 454.2. ¹H NMR (400 MHz, DMSO-d6): δ 10.44 (s, 1H), 8.59 (d,J=7.2 Hz, 1H), 8.00 (s, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 6.78 (d, J=6.8Hz, 1H), 3.91-3.88 (m, 2H), 3.74 (t, J=6.8 Hz, 2H), 3.28 (s, 2H),2.96-2.93 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 2.61-2.59 (m, 2H), 2.42 (brs,1H), 2.02-1.80 (m, 5H), 1.58-1.48 (m, 4H), 1.35-1.28 (m, 2H), 1.20 (s,6H).

Example 137. Preparation of1-(5-((1-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 136, wherein2-(tetrahydro-2H-pyran-4-yl)acetic acid was used in place oftetrahydro-2H-pyran-4-carboxylic acid. LCMS [M+H]⁺: 468.3. ¹H NMR (400MHz, DMSO-d6) δ 10.44 (s, 1H), 8.60 (d, J=7.1 Hz, 1H), 8.28 (t, J=8.3Hz, 1H), 8.00 (s, 1H), 7.36 (s, 1H), 6.78 (d, J=7.1 Hz, 1H), 3.84-3.72(m, 4H), 3.47 (s, 1H), 3.29 (t, J=11.4 Hz, 2H), 2.90 (q, J=11.7 Hz, 2H),2.78 (t, J=6.7 Hz, 2H), 2.61 (d, J=6.4 Hz, 2H), 1.92 (s, 2H), 1.85 (d,J=14.6 Hz, 2H), 1.68-1.52 (m, 5H), 1.46 (t, J=12.9 Hz, 2H), 1.38-1.13(m, 3H), 1.30 (s, 6H).

Example 138. Preparation of1-(5-((1-(2-cyclobutylpropan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 136, wherein cyclobutanecarboxylicacids was used in place of tetrahydro-2H-pyran-4-carboxylic acid. LCMS[M+H]⁺: 424.3. ¹H NMR (400 MHz, Methanol-d4) δ 8.43 (d, J=7.2 Hz, 1H),8.01 (s, 1H), 7.36 (s, 1H), 7.08 (s, 1H), 6.83 (dd, J=7.1, 1.9 Hz, 1H),3.89 (t, J=6.8 Hz, 2H), 3.58-3.48 (m, 2H), 2.97-2.86 (m, 3H), 2.82-2.74(m, 1H), 2.68 (d, J=6.7 Hz, 1H), 2.64 (d, J=5.9 Hz, 2H), 2.09-1.90 (m,6H), 1.50-1.26 (m, 10H).

Example 139. Preparation of1-(5-((1-(2,4-dimethylpentan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 136, wherein 3-methylbutanoic acidwas used in place of tetrahydro-2H-pyran-4-carboxylic acid. LCMS [M+H]⁺:426.3. ¹H NMR (300 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.43 (d, J=7.2 Hz,1H), 8.01 (s, 1H), 7.38 (s, 1H), 6.84 (d, J=7.3 Hz, 1H), 3.89 (t, J=6.8Hz, 2H), 3.71-3.48 (m, 3H), 2.97 (t, J=12.2 Hz, 2H), 2.89 (t, J=6.6 Hz,3H), 2.69 (d, J=6.3 Hz, 2H), 2.00 (d, J=13.2 Hz, 3H), 1.75 (hept, J=6.3Hz, 1H), 1.63 (d, J=5.4 Hz, 2H), 1.61-1.49 (m, 3H), 1.41 (s, 6H), 1.03(d, J=6.6 Hz, 6H). NH proton not observed due to solvent exchange.

Example 140. Preparation of1-(5-((1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 136, wherein4,4-difluorocyclohexane-1-carboxylic acid was used in place oftetrahydro-2H-pyran-4-carboxylic acid. LCMS [M+H]⁺: 488.4. ¹H NMR (400MHz, CD₃OD): δ 8.43 (d, J=7.2 Hz, 1H), 8.00 (s, 1H), 7.35 (s, 1H), 6.82(dd, J=7.6 Hz, 2.0 Hz, 1H), 3.87 (t, J=6.8 Hz, 2H), 3.59 (d, J=12.4 Hz,2H), 3.06-2.98 (m, 2H), 2.87 (t, J=6.8 Hz, 2H), 2.70 (d, J=6.8 Hz, 2H),2.08-2.10 (m, 2H), 2.01-1.75 (m, 8H), 1.64-1.46 (m, 4H), 1.33 (m, 6H).NH proton not observed due to solvent exchange.

Example 141. Preparation of1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl(S)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate

A solution of KOtBu (63.78 mL, 63.78 mmol, 1M in THF) was added dropwiseto a stirred suspension of (methoxymethyl)triphenylphosphonium chloride(21.86 g, 63.78 mmol) in THF (70 mL) at 0° C. The red solution wasstirred for 30 min at rt and then cooled again to 0° C. A solution oftert-butyl (S)-2-methyl-4-oxopiperidine-1-carboxylate (8.0 g, 37.5 mmol)in THF (30 mL) was added and the reaction mixture was stirred at rt for16 h. The reaction mixture was quenched with a solution of saturatedaqueous NH₄Cl and extracted with EtOAc. The organic layer was washedwith brine, dried over Na₂SO₄, filtered and concentrated. The crudematerial was purified by silica gel chromotography (eluting with 15-20%EtOAc in hexanes) to afford tert-butyl(S)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate (7.5 g, 31mmol, 82% yield) as a mixture of E:Z isomers. LCMS [M+H-tBu]⁺: 186. ¹HNMR (300 MHz, CDCl₃) δ 5.96 (s, 1H), 5.78 (s, 1H), 4.46-4.39 (m, 2H),4.00-3.89 (m, 2H), 3.56 (s, 3H), 3.53 (s, 3H), 2.86-2.74 (m, 2H),2.62-2.47 (m, 2H), 2.31-2.24 (m, 1H), 2.02-1.94 (m, 4H), 1.90-1.81 (m,3H), 1.46 (s, 18H) 1.04 (d, J=6.6 Hz, 3H).

Step 2. tert-butyl (2S)-4-formyl-2-methylpiperidine-1-carboxylate

A solution of HCl (2.0 M in water, 75 mL) was added to a solution oftert-butyl (S)-4-(methoxymethylene)-2-methylpiperidine-1-carboxylate(7.5 g, 31 mmol) in MeCN (220 mL) at rt. The reaction was heated to 40°C. and stirred for 40 min. The reaction was then cooled to rt andquenched by addition of solid NaHCO₃. Brine was added and the reactionwas extracted with EtOAc 3 times. The combined organic layers were driedover Na₂SO₄, filtered and concentrated to give crude tert-butyl(2S)-4-formyl-2-methylpiperidine-1-carboxylate as a ˜5:1 mixture ofcis:trans isomers (7 g, 31 mmol). The crude material was used in thenext reaction without further purification. LCMS [M+H-tBu]⁺: 172.

Step 3. tert-butyl(2S,4R)-4-(hydroxymethyl)-2-methylpiperidine-1-carboxylate

NaOMe (335 mg, 6.15 mmol) was added to a stirred solution of crudetert-butyl (2S)-4-formyl-2-methylpiperidine-1-carboxylate (7 g, 31 mmol)in MeOH (70 mL) at 0° C. The reaction mixture was kept at 4° C. for 24h. After 24 h the reaction mixture was placed in an ice bath, NaBH₄(4.65 g, 123 mmol) was added at 0° C. and the reaction was then stirredat rt for 10 min. The reaction mixture was quenched with water andextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedby silica gel chromotography (eluted with 20% EtOAc in hexanes) toafford tert-butyl(2S,4R)-4-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (5.4 g, 76%yield). LCMS [M+H-tBu]⁺: 174. ¹H NMR (400 MHz, CDCl₃) δ 4.45-4.41 (m,1H), 3.99-3.94 (m, 1H), 3.38-3.35 (m, 2H), 2.90 (brs, 1H), 1.87-1.84 (m,1H), 1.75-1.72 (m, 1H), 1.65-1.62 (m, 1H), 1.46 (s, 9H), 1.32-1.25 (m,2H), 1.17 (d, J=6.4 Hz, 3H), 1.05-1.01 (s, 1H).

Step 4. tert-butyl(2S,4R)-4-(bromomethyl)-2-methylpiperidine-1-carboxylate

Triphenylphosphine dibromide (1.2 g, 28.5 mmol) was added to a solutionof imidazole (2.10 g, 30.6 mmol) and tert-butyl(2S,4R)-4-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (5.4 g, 23.5mmol in DCM (50 mL) at 0° C. The reaction mixture was stirred at rt for16 h. After completion of the reaction, the mixture was diluted with DCMand washed with water. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedby silica gel chromotography (eluted with 10% EtOAc in hexanes) toafford tert-butyl(2S,4R)-4-(bromomethyl)-2-methylpiperidine-1-carboxylate (3.5 g, 12.2mmol, 50% yield). LCMS [M+H-tBu]⁺: 236. ¹H NMR (300 MHz, CDCl₃) δ 4.45(brs, 1H), 4.01 (brs, 1H), 3.30-3.20 (m, 2H), 2.88-2.80 (m, 1H),2.04-1.94 (m, 1H), 1.85-1.81 (m, 1H), 1.70-1.65 (m, 1H), 1.29-1.03 (m,15H).

Step 5. tert-butyl(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate

Zn powder was activated by taking commercial material and stirring itvigorously in a solution of aqueous 1M HCl for 10 min. The material wasthen filtered and the large chunks were broken up with a spatula. Thesolids were washed with distilled water, followed by EtOH, followed byEt₂O. The solids were then heated at 50° C. overnight under vacuum.

To an oven-dried 2-necked flask was added tert-butyl(2S,4R)-4-(bromomethyl)-2-methylpiperidine-1-carboxylate (2.98 g, 10.2mmol),1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(3.90 g, 8.5 mmol), NiCl₂(DME) (0.093 g, 0.425 mmol),pyridine-2,6-bis(carboximidamide) dihydrochloride (0.100 g, 0.425 mmol),Zn powder (1.11 g, 17.0 mmol) and sodium iodide (0.319 g, 2.125 mmol).The flask was sealed with a septum and evacuated and refilled with argon3 times. DMA (34.0 mL, degassed by bubbling argon through for severalmin) was added and the reaction was stirred at 70° C. overnight. Thereaction was cooled to rt and poured into water and a grey precipitateformed which was collected by filtration. The solid was diluted withEtOH (200 mL) and filtered through celite (washed with EtOH) to removeZn solids. The filtrate was concentrated and the crude material waspurified by silica gel chromatography (eluted with 10-100% of (3:1EtOAc/EtOH w/0.1% Et₃N)/heptane) to give tert-butyl(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate(4.30 g, 6.69 mmol, 79% yield) as an off-white solid. LCMS [M+H-Boc]⁺:492.2.

Step 6.3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride

A solution of HCl (4.0 M in dioxane, 40 mL) was added to tert-butyl(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate(5.1 g, 8.61 mmol) and the mixture was stirred at rt for 3 h and thenconcentrated. The crude compound was triturated with diethyl ether toafford3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (4.8 g, crude). LCMS [M+H]⁺: 492.3.

Step 7.1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

TEA (3.3 mL, 23.7 mmol) and 4,4-difluorocyclohexane-1-carbaldehyde (1.4g, 9.48 mmol) were added to a solution of3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (2.5 g, 4.74 mmol) in DCM (25 mL) at rt and the mixturewas stirred for 1.5 h. The reaction was then cooled to 0° C. and sodiumtriacetoxyborohydride (2.00 g, 9.48 mmol) was added. The reactionmixture was stirred for 16 h at rt. After completion, the reaction wasdiluted with DCM and water and the organic layer was dried over Na₂SO₄,filtered and concentrated to afford crude1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(1.7 g, crude). LCMS [M+H]⁺: 624.5.

Step 8.1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (3 mL) was added to crude1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.The reaction mixture was stirred for 16 h at 90° C. and thenconcentrated. The crude compound was purified by reverse-phase HPLCusing: Mobile Phase: A=0.1% HCOOH in WATER, B=Acetonitrile, Column: XSELECT (250 mm×21.2 mm), 5.0 μm, Flow: 20 mL/min. The collectedfractions were concentrated under reduced pressure to obtain the productas a formate salt. The product was dissolved in 20% MeOH in DCM, washedwith a solution of saturated aqueous NaHCO₃ and concentrated to give1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(554 mg, 1.05 mmol, 48% yield) as an off-white solid. HPLC: 98.40%[Rt=4.893 min]. LCMS [M+H]: 474.5. H NMR (500 MHz, DMSO-d6) δ 10.42 (s,1H), 8.54 (d, J=7.1 Hz, 1H), 7.98 (s, 1H), 7.34 (d, 1H), 6.78 (dd,J=7.3, 1.9 Hz, 1H), 3.76 (t, J=6.7 Hz, 2H), 2.91 (3, 1H), 2.79 (t, J=6.7Hz, 2H), 2.53 (d, J=9.4 Hz, 2H), 2.45-2.34 (m, 2H), 2.27-2.12 (m, 2H),2.04-1.92 (m, 2H), 1.92-1.85 (i, 1H), 1.85-1.67 (i, 4H), 1.60-1.47 (m,2H), 1.47-1.35 (m, 2H), 1.24-1.14 (i, 1H), 1.13-1.00 (m, 2H), 0.88 (d,J=6.5 Hz, 3H).

The compounds in the following table were prepared by the method ofExample 141, using the appropriate commercially available aldehyde instep 7.

Example Mass No. Structure [M + H]⁺ ¹H NMR 142

440.5 (500 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.54 (d, J = 7.1 Hz, 1H), 7.98(s, 1H), 7.34 (s, 1H), 6.77 (dd, J = 7.2, 1.9 Hz, 1H), 3.82 (d, J = 11.3Hz, 2H), 3.76 (t, J = 6.7 Hz, 2H), 3.26 (t, J = 11.5 Hz, 2H), 3.18 (d, J= 5.3 Hz, 1H), 2.91 (d, J = 6.2 Hz, 1H), 2.78 (t, J = 6.7 Hz, 2H), 2.54(s, 1H), 2.46-2.33 (m, 2H), 2.19 (qd, J = 12.5, 6.9 Hz, 2H), 1.88 (s,1H), 1.56 (dd, J = 44.9, 16.0 Hz, 4H), 1.47-1.35 (m, 2H), 1.25-1.14 (m,1H), 1.14-1.00 (m, 2H), 0.88 (d, J = 6.5 Hz, 3H). 143

438.3 (400 MHz, METHANOL-d4) δ = 8.40 (d, J = 7.2 Hz, 1H), 7.98 (s, 1H),7.33 (s, 1H), 6.81-6.79 (m, 1H), 3.89-3.86 (m, 2H), 3.04 (br d, J = 12.0Hz, 1H), 2.89-2.87 (m, 2H), 2.66-2.56 (m, 3H), 2.20-1.84 (m, 4H),1.75-1.44 (m, 8H), 1.37-1.11 (m, 5H), 1.10-1.03 (m, 3H), 0.99-0.81 (m,2H) 144

424.5 (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.52 (d, J = 7.1 Hz, 1H), 7.96(s, 1H), 7.33 (s, 1H), 6.76 (d, J = 7.1 Hz, 1H), 3.75 (t, J = 6.7 Hz,2H), 3.29 (s, 1H), 2.93 (s, 1H), 2.77 (t, J = 6.7 Hz, 2H), 2.50 (p, J =1.8 Hz, 3H), 2.28-2.13 (m, 2H), 2.02-1.93 (m, 1H), 1.86 (s, 1H),1.70-1.05 (m, 13H), 0.86 (d, J = 6.6 Hz, 3H). 145

398.4 (500 MHz, Methanol-d4) δ 8.41 (d, J = 7.2 Hz, 1H), 7.99 (s, 1H),7.35 (d, J = 1.8 Hz, 1H), 6.82 (dd, J = 7.2, 1.8 Hz, 1H), 3.89 (t, J =6.8 Hz, 2H), 3.09-2.98 (m, 1H), 2.90 (t, J = 6.8 Hz, 2H), 2.64-2.60 (m,2H), 2.59-2.51 (m, 2H), 2.30-2.18 (m, 2H), 2.05-1.95 (m, 1H), 1.82-1.72(m, 1H), 1.68-1.61 (m, 1H), 1.59-1.50 (m, 2H), 1.43-1.33 (m, 1H), 0.99(d, J = 6.6 Hz, 3H), 0.93 (d, J = 4.0 Hz, 3H), 0.92 (d, J = 4.1 Hz, 3H).146

410.5 (400 MHz, DMSO-d6) δ 10.45 (d, J = 3.9 Hz, 1H), 8.58 (d, J = 7.1Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.35 (d, J = 5.1 Hz, 1H), 6.79 (d, J= 7.7 Hz, 1H), 3.76 (td, J = 6.8, 3.0 Hz, 2H), 3.54 (d, J = 47.4 Hz,2H), 3.38-3.17 (m, 2H), 3.16-2.94 (m, 3H), 2.77 (t, J = 6.8 Hz, 2H),2.73-2.59 (m, 2H), 2.18-1.98 (m, 3H), 1.95-1.53 (m, 7H), 1.25 (m, 3H).147

452.4 (400 MHz, CD₃OD) δ 8.43 (d, J = 6.8 Hz, 1H), 8.00 (s, 1H), 7.36(s, 1H), 6.81 (dd, J = 7.2 Hz, 2.0 Hz, 1H), 3.89 (t, J = 6.4 Hz, 2H),3.12 (bm, 2H), 2.90-2.68 (m, 5H), 2.20 (bm, 2H), 1.81-1.30 (m, 21H). NHproton not observed due to solvent exchange 148

454.1 (300 MHz, CD₃OD) δ 8.49 (s, 1H), 8.43 (d, J = 7.2 Hz, 1H), 8.00(s, 1H), 7.36 (s, 1H), 6.83 (d, J = 6.0 Hz, 1H), 3.93-3.86 (m, 4H), 3.60(s, 1H), 3.46-3.36 (m, 3H), 3.23 (s, 2H), 3.08-3.04 (m, 3H), 2.88 (t, J= 6.6 Hz, 2H), 2.69-2.67 (m, 2H), 2.02-1.98 (s, 1H), 1.84-1.63 (m, 7H),1.32-1.30 (m, 5H). 149

466.2 (300 MHz, Methanol-d4) δ 8.43 (m, 2H), 8.01 (s, 1H), 7.36 (d, J =1.8 Hz, 1H), 6.83 (dd, J = 7.2, 1.8 Hz, 1H), 3.88 (t, J = 6.8 Hz, 2H),3.71 (s, 1H), 3.24 (m, 2H), 2.96 (s, 1H), 2.88 (t, J = 6.8 Hz, 2H), 2.69(s, 2H), 2.22 (s, 1H), 1.73 (dd, J = 59.4, 16.0 Hz, 7H), 1.53-1.16 (m,10H), 0.93 (d, J = 3.0 Hz, 6H). 150

433.0 (300 MHz, CD₃OD) δ 8.60 (s, 1H), 8.53-8.51 (m, 1H), 8.42-8.39 (m.2H), 7.98 (s, 1H), 7.96-7.94 (m, 1H), 7.48-7.46 (m, 1H), 7.34 (s, 1H),6.84 (d, J = 7.5 Hz, 1.3 Hz, 1H), 4.04-4.02 (m, 2H) 3.87 (t, J = 6.9 Hz,2H), 2.91-2.85 (m, 4H), 2.67-2.65 (m, 3H), 2.18-2.16 (s, 2H), 1.71-1.69(m, 3H), 1.28 (s, 3H).

Example 151. Preparation of1-(5-((1-(((1r,4r)-4-hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 141, steps 7-8, whereintrans-4-(benzyloxy)cyclohexane-1-carbaldehyde [see WO2020/232470, 2020,A1] was used in place of 4,4-difluorocyclohexane-1-carbaldehyde. LCMS[M+H]⁺: 440.1. ¹H NMR (400 MHz, CD₃OD) b 8.42 (s, 1H), 8.00 (s, 1H),7.36 (s, 1H), 6.98 (d J=5.6 Hz, 1H), 3.87 (t, J=6.8 Hz, 2H), 3.56-3.48(m, 2H), 2.93-2.85 (m, 6H), 2.68-2.65 (m, 2H), 1.97-1.80 (m, 7H),1.58-1.55 (m, 2H), 1.29, 1.27 (m, 4H), 1.11-1.08 (m, 2H), NH and OHprotons not observed due to solvent exchange.

Example 152. Preparation of1-(5-(((2S,4R)-1-((3,3-difluorocyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (see Example 141, step 6) using the method of Example 1,steps 4 to 5, wherein 3-(bromomethyl)-1,1-difluorocyclobutane was usedin place of (bromomethyl)cyclohexane. LCMS [M+H]⁺: 446.3. ¹H NMR (400MHz, CD₃OD) δ 8.51 (s, 1H), 8.43 (d, J=7.1 Hz, 1H), 8.00 (s, 1H), 7.36(s, 1H), 6.83 (dd, J=7.2, 1.9 Hz, 1H), 3.89 (t, J=6.8 Hz, 2H), 3.48 (m,1H), 3.08 (d, J=41.8 Hz, 3H), 2.89 (t, J=6.8 Hz, 2H), 2.76 (d, J=7.6 Hz,2H), 2.68 (d, J=7.2 Hz, 2H), 2.43 (d, J=29.2 Hz, 3H), 2.18 (d, J=10.5Hz, 1-H), 1.90-1.62 (m, 3H), 1.51 (d, 1H), 1.37-1.17 (i, 4H). NH protonnot observed due to solvent exchange.

The compounds in the following table were prepared from tert-butyl(R)-2-methyl-4-oxopiperidine-1-carboxylate using the method of Example141, wherein the appropriate commercially available aldehydes were usedin step 7.

Example Mass No. Structure [M + H]⁺ ¹H NMR 153

398.2 (400 MHz, CD₃OD) δ 8.49 (s, 1H), 8.44 (d, J = 6.8 Hz, 1H), 7.98(s, 1H), 7.35 (s, 1H), 6.81 (d, J = 6.0 Hz, 1H), 3.94-3.84 (m, 4H), 3.65(s, 1H), 3.45-3.40 (m, 2H), 3.17 (s, 2H), 2.91-2.84 (m, 3H), 2.67-2.63(m, 2H), 2.09 (s, 1H), 2.01 (s, 1H), 1.85-1.58 (m, 5H), 1.39-1.30 (m,6H). 154

440.1 (400 MHz, CD₃OD) δ 8.51 (s, 1H), 8.41 (d, J = 7.2 Hz, 1H), 7.98(s, 1H), 7.34 (s, 1H), 6.82-6.80 (m, 1H), 3.86 (t, J = 6.4 Hz, 2H), 3.68(s, 1H), 3.19 (s, 2H), 2.88-2.84 (s, 4H), 2.68-2.66 (m, 2H), 2.19 (s,1H), 2.08-2.02 (m, 1H) 1.86-1.72 (m, 4H), 1.64-1.60 (m, 2H), 1.33-1.27(m, 3H, 1.04-1.00 (m, 6H). 155

474.4 (400 MHz, CD₃OD) δ 8.52 (s, 1H), 8.41 (d, J = 6.8 Hz, 1H), 7.99(s, 1H), 7.34 (s, 1H), 6.83-6.81 (m, 1H), 3.87 (t, J = 7.2 Hz, 2H),2.89-2.86 (m, 3H), 2.66-2.65 (m, 2H), 2.12-2.04 (m, 4H), 1.88-1.70 (m,7H), 1.50 (brs, 2H), 1.20 (s, 3H).

Example 156. Preparation of1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1: tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate

To a suspension of1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(45 mg, 0.098 mmol) in toluene (2 mL) and water (0.2 mL) at roomtemperature was added Cs₂CO₃ (128 mg, 0.392 mmol), potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate (60.0mg, 0.196 mmol) and RuPhos (9.14 mg, 0.020 mmol), followed by Pd(OAc)₂(2.2 mg, 9.8 μmol). The mixture was stirred at 90° C. for 3 h, thencooled to rt and partitioned between EtOAc and water. The organic layerwas separated, washed with brine, dried over sodium sulfate, filteredand concentrated to give crude tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate(56 mg, 0.098 mmol). LCMS [M+H]⁺: 579.4. The crude material was usedwithout further purification.

Step 2:3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride

A solution of HCl (4.0 M in dioxane, 2 mL, 8 mmol) was added totert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate(55 mg, 0.095 mmol) and the mixture was stirred for 2 h at rt. Thereaction was then concentrated to give crude3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (46 mg, 0.095 mmol) which was used without furtherpurification. LCMS [M+H]⁺: 479.4.

Step 3:1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

To a solution of3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (22 mg, 0.043 mmol) in DMF (1 mL) was added potassiumcarbonate (30 mg, 0.21 mmol) and (bromomethyl)cyclohexane (0.012 mL,0.085 mmol). The mixture was heated at 80° C. for 4 h and then cooled tort. The mixture was diluted with ethyl acetate and washed sequentiallywith water and brine. The organic layer was dried over sodium sulfate,filtered and concentrated to give crude1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(25 mg, 0.043 mmol) which was used without further purification. LCMS[M+H]⁺: 575.4.

Step 4:1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (1.5 mL, 19 mmol) was added to crude1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(24 mg, 0.042 mmol) and the mixture was heated at 80° C. overnight. Themixture was then cooled to rt, concentrated and the residue wasdissolved in toluene and concentrated again. The residue was dissolvedin DMSO, filtered through a 1 micron filter and purified by reversephase HPLC using ACN/Water/0.1% TFA. The fractions containing theproduct were combined, frozen and lyophilized to afford a TFA salt of1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(5.5 mg, 10 umol, 24% yield). LCMS [M+H]⁺: 425.3. ¹H NMR (500 MHz,DMSO-d6) δ 10.48 (s, 1H), 8.66 (d, J=7.2 Hz, 1H), 8.06 (s, 1H), 7.53 (s,1H), 6.91 (d, J=6.9 Hz, 1H), 4.59 (s, 6H), 3.80 (t, J=6.7 Hz, 2H), 3.72(s, 1H), 3.47 (s, 1H), 3.01 (s, 4H), 2.80 (t, J=6.7 Hz, 2H), 1.69 (td,J=29.6, 13.7 Hz, 6H), 1.21 (dq, J=36.0, 12.2 Hz, 3H), 0.95 (q, J=11.9Hz, 2H).

The compounds in the following table were prepared by the method ofExample 156, using the appropriate commercially available halide,mesylate or triflate in step 4.

Example Mass No. Structure [M + H]⁺ ¹H NMR 157

461.4 (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.67 (d, J = 7.2 Hz, 1H), 8.07(s, 1H), 7.55 (s, 1H), 7.01-6.71 (m, 1H), 3.79 (d, J = 6.7 Hz, 4H), 3.49(d, J = 29.6 Hz, 4H), 3.02 (s, 6H), 2.80 (t, J = 6.7 Hz, 2H, 2.04 (d, J= 9.1 Hz, 2H), 1.94-1.66 (m, 5H), 1.23 (d, J = 12.9 Hz, 2H). 158

439.3 (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.66 (d, J = 7.2 Hz, 1H), 8.07(s, 1H), 7.54 (s, 1H), 6.91 (dd, J = 7.1, 1.8 Hz, 1H), 4.27 (s, 4H),3.80 (t, J = 6.7 Hz, 4H), 3.57-3.32 (m, 2H), 2.95 (d, J = 71.8 Hz, 5H),2.80 (t, J = 6.7 Hz, 2H), 1.72 (ddt, J = 13.8, 6.8, 3.1 Hz, 2H),1.67-1.51 (m, 4H), 1.52-1.38 (m, 4H), 1.27-1.13 (m, 2H). 159

411.2 (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.67 (d, J = 7.1 Hz, 1H), 8.07(s, 1H), 7.56 (s, 1H), 6.92 (dd, J = 7.1, 1.9 Hz, 1H), 4.85 (s, 4H),3.80 (t, J = 6.7 Hz, 4H), 3.51 (s, 1H), 3.09 (s, 5H), 2.80 (t, J = 6.7Hz, 2H), 2.20 (p, J = 7.7 Hz, 1H), 1.94-1.71 (m, 2H), 1.70-1.39 (m, 4H),1.37-1.06 (m, 2H). 160

427.3 (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.68 (dd, J = 7.1, 0.9 Hz,1H), 8.08 (s, 1H), 7.58 (s, 1H), 6.93 (dd, J = 7.2, 1.9 Hz, 1H),3.97-3.70 (m, 6H), 3.65-3.36 (m, 2H), 3.31 (td, J = 11.7, 2.0 Hz, 2H),3.03 (d, J = 59.1 Hz, 6H), 2.80 (t, J = 6.7 Hz, 4H), 2.01 (s, 1H), 1.63(ddd, J = 12.9, 4.1, 2.0 Hz, 2H), 1.34-1.07 (m, 2H). 161

441.2 (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.65 (dd, J = 7.2, 0.9 Hz,1H), 8.06 (s, 1H), 7.52 (s, 1H), 6.90 (dd, J = 7.1, 1.8 Hz, 1H), 4.45(t, J = 6.5 Hz, 1H), 3.86-3.78 (m, 4H), 3.45 (t, J = 6.6 Hz, 2H, 3.27(tdd, J = 11.7, 4.2, 2.0 Hz, 4H), 3.08 (d, J = 47.4 Hz, 4H), 2.80 (t, J= 6.7 Hz, 2H), 1.62-1.51 (m, 5H), 1.36 (q, J = 6.7 Hz, 1H), 1.26-1.08(m, 4H). 162

427.2 (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.67 (d, J = 7.1 Hz, 1H), 8.08(s, 1H), 7.57 (s, 1H), 6.92 (dd, J = 7.2, 1.8 Hz, 1H), 5.00 (s, 6H),4.01-3.76 (m, 4H), 3.71 (dt, J = 11.3, 4.2 Hz, 1H), 3.36 (ddd, J = 11.2,9.7, 3.0 Hz, 2H), 3.31-2.84 (m, 5H), 2.80 (t, J = 6.7 Hz, 2H), 1.98 (s,1H), 1.87-1.76 (m, 1H, 1.66-1.38 (m, 2H), 1.38-1.17 (m, 1H). 163

371.2 (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.63 (d, J = 7.1 Hz, 1H), 8.04(d, J = 2.4 Hz, 1H), 7.51 (s, 1H), 6.89 (dd, J = 7.2, 1.8 Hz, 1H), 4.41(s, 3H), 3.78 (dd, J = 7.8, 5.7 Hz, 2H), 3.69 (s, 2H), 3.45 (s, 2H),3.02 (d, J = 8.5 Hz, 5H), 2.78 (td, J = 6.7, 2.2 Hz, 2H), 1.71-1.47 (m,2H), 0.90 (t, J = 7.3 Hz, 3H). 164

399.3 (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.65 (d, J = 6.7 Hz, 1H), 8.06(d, J = 4.9 Hz, 1H), 7.57 (d, J = 37.0 Hz, 1H), 6.92 (d, J = 7.1 Hz,1H), 4.56-3.26 (m, 8H), 3.05 (s, 5H), 2.80 (t, J = 6.7 Hz, 2H, 1.77 (s,2H), 1.61 (s, 2H), 0.94 (t, J = 7.4 Hz, 6H). 165

419.3 (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.67 (d, J = 7.2 Hz, 1H), 8.08(s, 1H), 7.56 (s, 1H), 7.48 (d, J = 4.8 Hz, 5H), 6.92 (dd, J = 7.2, 1.8Hz, 1H), 4.24 (s, 2H), 3.79 (t, J = 6.7 Hz, 4H), 3.00 (d, J = 92.9 Hz,5H), 2.79 (t, J = 6.7 Hz, 3H), 2.56 (s, 2H). 166

371.2 (500 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.65 (dd, J = 7.1, 0.9 Hz,1H), 8.06 (s, 1H), 7.54 (s, 1H), 6.92 (dd, J = 7.2, 1.8 Hz, 1H), 4.56(s, 2H), 3.88-3.65 (m, 4H), 3.60-3.33 (m, 3H), 3.07 (s, 4H, 2.80 (t, J =6.7 Hz, 2H), 1.26 (d, J = 6.6 Hz, 6H). 167

433.4 (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.69 (d, J = 7.1 Hz, 1H), 8.09(s, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 7.28 (dt, J = 14.0, 7.1 Hz, 3H),7.01-6.83 (m, 1H), 4.27 (s, 4H), 3.80 (t, J = 6.7 Hz, 4H), 3.02 (d, J =112.7 Hz, 6H), 2.79 (t, J = 6.7 Hz, 2H), 2.38 (s, 3H). 168

437.2 (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.67 (d, J = 7.2 Hz, 1H), 8.07(s, 1H), 7.63-7.45 (m, 3H), 7.30 (t, J = 8.6 Hz, 2H), 6.92 (dd, J = 7.2,1.8 Hz, 1H), 4.20 (s, 2H), 3.79 (t, J = 6.7 Hz, 6H), 3.08 (s, 6H), 2.79(t, J = 6.7 Hz, 2H). 169

403.2 (400 MHz, DMSO-d6) δ 10.50 (s, 1H), 8.73 (d, J = 7.1 Hz, 1H), 8.12(s, 1H), 7.65 (d, J = 34.0 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 3.81 (q, J= 6.0, 5.3 Hz, 6H), 3.07 (s, 8H), 2.79 (dd, J = 7.4, 6.0 Hz, 2H), 1.34(d, J = 21.4 Hz, 6H). 170

437.3 (500 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.69 (d, J = 7.1 Hz, 1H), 8.09(s, 1H), 7.60 (s, 1H), 7.50 (td, J = 7.9, 6.1 Hz, 1H), 7.37-7.15 (m,3H), 6.94 (dd, J = 7.3, 1.8 Hz, 1H), 4.67 (s, 2H), 4.05 (d, J = 80.5 Hz,4H), 3.80 (t, J = 6.7 Hz, 2H), 2.98 (d, J = 72.5 Hz, 6H), 2.79 (t, J =6.7 Hz, 2H). 171

411.3 (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.77 (d, J = 7.3 Hz, 1H), 8.15(s, 1H), 7.72 (s, 1H), 6.98 (d, J = 7.2 Hz, 1H), 4.39 (s, 2H), 3.82 (t,J = 6.7 Hz, 2H), 3.33 (s, 4H), 3.10 (dd, J = 47.4, 18.5 Hz, 4H, 2.79 (t,J = 6.7 Hz, 2H), 2.68 (d, J = 37.2 Hz, 2H). 172

451.2 (500 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.76 (d, J = 7.1 Hz, 1H), 8.15(s, 1H), 7.73 (s, 1H), 7.00 (dd, J = 7.2, 1.8 Hz, 1H), 4.53 (d, J =195.2 Hz, 8H), 3.83 (t, J = 6.7 Hz, 2H), 3.21 (d, J = 131.0 Hz, 4H, 2.80(t, J = 6.7 Hz, 2H), 1.01 (s, 2H), 0.79 (s, 2H). 173

443.3 (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.70 (d, J = 7.1 Hz, 1H), 8.07(s, 1H), 7.66 (s, 1H), 6.91 (d, J = 7.2 Hz, 1H), 6.44 (tt, J = 52.3, 5.3Hz, 1H), 4.31 (s, 2H), 3.75 (t, J = 6.7 Hz, 2H), 3.31 (s, 2H, 3.05 (t, J= 15.1 Hz, 4H), 2.93 (d, J = 12.8 Hz, 2H), 2.72 (t, J = 6.7 Hz, 2H),2.67-2.53 (m, 2H). 174

433.4 (400 MHz, Methanol-d4) δ 8.48 (d, J = 7.2 Hz, 1H), 8.04 (s, 1H),7.54 (s, 1H), 6.99 (dd, J = 7.2, 1.9 Hz, 1H), 4.88 (br. s, 2H), 3.90 (t,J = 6.8 Hz, 2H), 3.76 (s, 2H), 3.58-3.37 (m, 2H), 3.30-3.22 (m, 1H),3.22-3.01 (m, 4H), 2.89 (t, J = 6.8 Hz, 2H), 2.87-2.74 (m, 2H),2.67-2.52 (m, 2H), 2.52-2.36 (m, 2H). NH proton not observed due tosolvent exchange 175

434.3 (500 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.79-8.60 (m, 3H), 8.14-7.98(m, 2H), 7.76-7.58 (m, 2H), 6.95 (dd, J = 7.1, 1.9 Hz, 1H), 4.14 (s,6H), 3.80 (t, J = 6.7 Hz, 2H), 3.52-2.84 (m, 5H), 2.79 (t, J = 6.7 Hz,2H), 1.48 (s, 3H). 176

420.3 (500 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.80-8.61 (m, 3H), 8.14 (s,1H), 7.70 (s, 3H), 6.99 (d, J = 7.0 Hz, 1H), 4.45 (s, 4H), 4.28 (s, 4H),3.82 (t, J = 6.7 Hz, 2H), 3.00 (s, 4H), 2.80 (t, J = 6.7 Hz, 2H). 177

413.4 (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.67 (d, J = 7.1 Hz, 1H), 8.07(s, 1H), 7.56 (s, 1H), 6.92 (dd, J = 7.2, 1.9 Hz, 1H), 4.61 (s, 4H),3.92-3.71 (m, 6H), 3.64 (dt, J = 8.4, 7.4 Hz, 1H), 3.57-3.43 (m, 1H),3.39 (dd, J = 8.6, 6.4 Hz, 1H), 3.08 (s, 5H), 2.80 (t, J = 6.7 Hz, 2H),2.64-2.56 (m, 1H), 2.07 (td, J = 12.7, 7.7 Hz, 1H), 1.59 (dq, J = 12.3,7.4 Hz, 1H). 178

433.3 (400 MHz, CDCI3) δ 8.42-8.29 (m, 1H), 7.93 (s, 1H), 7.66 (br s,1H), 7.34-7.27 (m, 3H), 7.25-7.17 (m, 3H), 6.91-6.89 (m, 1H), 3.90 (t, J= 6.8 Hz, 2H), 3.56 (s, 2H), 2.97-2.86 (m, 4H), 2.86-2.51 (m, 10H).

Examples 179 and 180. Preparation of1-(5-((4-(((1r,4r)-4-methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 179) and1-(5-((4-(((1s,4s)-4-methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example (180)

Prepared using the method of Example 156 using a commercially availablemixture of cis and trans 1-(bromomethyl)-4-methoxycyclohexane in placeof (bromomethyl)cyclohexane. The stereoisomers were purified after thefinal step by reverse-phase HPLC (eluting with using ACN/Water/0.1%TFA).

Example 179.1-(5-((4-(((1r,4r)-4-methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Eluted first, minor isomer. LCMS [M+H]⁺: 455.2. ¹H NMR (500 MHz,DMSO-d6) δ 10.48 (s, 1H), 8.66 (d, J=7.2 Hz, 1H), 8.07 (s, 1H), 7.54 (s,1H), 6.91 (dd, J=7.3, 1.8 Hz, 1H), 4.59 (s, 4H), 3.80 (t, J=6.7 Hz, 4H),3.42 (d, J=45.9 Hz, 1H), 3.24 (s, 3H), 3.06 (ddd, J=14.6, 10.7, 4.2 Hz,6H), 2.80 (t, J=6.7 Hz, 2H), 2.01 (d, J=12.1 Hz, 2H), 1.86-1.54 (m, 3H),1.20-0.77 (m, 4H).

Example 180.1-(5-((4-(((1s,4s)-4-methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Eluted second, major isomer. LCMS [M+H]⁺: 455.2. ¹H NMR (500 MHz,DMSO-d6) δ 10.48 (s, 1H), 8.66 (d, J=7.2 Hz, 1H), 8.07 (s, 1H), 7.54 (s,1H), 6.91 (dd, J=7.1, 1.8 Hz, 1H), 4.60 (s, 4H), 3.80 (t, J=6.7 Hz, 4H),3.47 (s, 1H), 3.38 (d, J=4.9 Hz, 1H), 3.21 (s, 3H), 3.02 (s, 5H), 2.80(t, J=6.7 Hz, 2H), 1.91-1.62 (m, 3H), 1.56-1.36 (m, 4H), 1.32-1.18 (m,2H).

Example 181. Preparation of1-(5-((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. (4-benzylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone

HATU (8.26 g, 21.9 mmol) and DIPEA (9.53 mL, 54.75 mmol) were added to asolution of 4,4-difluorocyclohexane-1-carboxylic acid (3.0 g, 18.25mmol) in THF (10 mL) at 0° C. The mixture was stirred for 10 min andthen 1-benzylpiperazine (3.2 g, 18.3 mmol) was added and the reactionwas stirred for 16 h at rt. The reaction mixture was quenched with waterand extracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄, filtered and concentrated. The crude material was purifiedby silica gel chromotography (eluting with 50% EtOAc in hexane) toafford (4-benzylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone (1.5 g,4.65 mmol, 25% yield). LCMS [M+H]⁺: 323.5.

Step 2. 1-benzyl-4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine

To a stirred solution of(4-benzylpiperazin-1-yl)(4,4-difluorocyclohexyl)methanone (1.5 g, 4.65mmol) in THF (10 mL) was added ZrCl₄ (1.84 g, 4.65 mmol) at −20° C. andthe mixture was stirred for 30 min. A solution of MeMgBr.Et₂O (9.4 mL,28.2 mmol, 3.0 M) was added and the mixture was stirred for 10 min at−20° C. and then at rt for 16 h. After completion, the reaction wasquenched with water (10 mL) and extracted with EtOAc. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated. Thecrude material was purified by silica gel chromotography (eluting with10-15% EtOAc in hexanes) to afford1-benzyl-4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine (500 mg,1.49 mmol, 31% yield).

Step 3. 1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine

To a stirred solution of1-benzyl-4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine (500 mg,1.49 mmol) in EtOAc (15 mL) under an inert atmosphere was added Pd/C(100 mg) at rt. The flask was evacuated and refilled with hydrogen froma balloon and stirred at RT for 36 h. The reaction was then purged withargon and filtered through celite. The filtrate was concentrated to givecrude 1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine (400 mg,crude). The material was used without further purification.

Step 4. potassium((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)trifluoroborate

To a stirred solution of1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazine (400 mg, 1.62 mmol)in THF (10 mL) at rt was added K₂CO₃ (448 mg, 3.25 mmol) and potassium(bromomethyl)trifluoroborate (326 mg, 1.62 mmol). The reaction wasstirred for 12 h at 80° C. and then cooled to rt and concentrated toafford potassium((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)trifluoroborate(1.5 g, crude). The material was used without further purification.

Step 5:1-(5-((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared from potassium((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)trifluoroborateby the method of Example 156, steps 1 and 4, wherein potassium((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)trifluoroboratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 489.2. ¹H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J=6.9 Hz, 1H),8.06 (s, 1H), 7.54 (d, J=14.9 Hz, 1H), 7.00 (dd, J=7.4, 1.8 Hz, 1H),3.91 (t, J=6.7 Hz, 2H), 3.48 (s, 3H), 3.26-3.10 (m, 2H), 2.89 (t, J=6.7Hz, 2H), 2.67 (s, 3H), 2.16 (d, J=23.5 Hz, 2H), 1.82 (d, J=14.0 Hz, 4H),1.55-1.18 (m, 7H). 4 protons not integrated due to peak broadening. NHproton not observed due to solvent exchange.

Example 182. Preparation of1-(5-((4-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of 181, whereintetrahydro-2H-pyran-4-carboxylic acid was used in place of4,4-difluorocyclohexane-1-carboxylic acid. LCMS [M+H]⁺: 474.8. ¹H NMR(400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.74, (s, 1H), 8.62 (s, 1H), 8.13(s, 1H), 8.03 (s, 1H), 7.48 (s, 1H), 6.90 (s, 1H), 3.89 (d, J=11.0 Hz,2H), 3.78 (t, J=6.5 Hz, 2H), 3.63 (s, 1H), 3.32 (s, 9H), 2.78 (t, J=6.7Hz, 2H), 1.85 (d, J=110.7 Hz, 2H), 1.52 (d, J=12.5 Hz, 2H), 1.43-1.07(m, 6H), 0.86 (s, 3H).

Example 183. Preparation of1-(5-((4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 106, wherein3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of3-(2,4-dimethoxybenzyl)-1-(5-((1-(2-hydroxy-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 401.4. ¹H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.66 (d,J=7.1 Hz, 1H), 8.07 (d, J=1.7 Hz, 1H), 7.56 (s, 1H), 6.92 (dd, J=7.3,1.9 Hz, 1H), 4.70 (s, 4H), 3.96-3.67 (m, 4H), 3.29 (s, 2H), 2.97 (d,J=36.7 Hz, 5H), 2.79 (t, J=6.8 Hz, 2H), 1.22 (d, J=1.8 Hz, 6H).

Example 184. Preparation of1-(5-((4-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 98, wherein3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride was used in place of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride and 1-(trifluoromethyl)cyclopropane-1-carboxylic acid wasused in place of isobutyric acid. LCMS [M+H]⁺: 465.2. ¹H NMR (400 MHz,DMSO-d6) δ 10.51 (d, J=2.2 Hz, 1H), 8.76 (d, J=7.1 Hz, 1H), 8.14 (d,J=1.9 Hz, 1H), 7.72 (s, 1H), 6.99 (dd, J=7.2, 2.0 Hz, 1H), 4.34 (s, 2H),3.82 (td, J=6.4, 1.8 Hz, 2H), 3.64 (s, 4H), 3.19 (s, 4H), 2.79 (t, J=6.7Hz, 2H), 1.47-0.84 (m, 4H).

Example 185. Preparation of1-(5-((4-(isopropylsulfonyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 80, wherein3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride was used in place of3-(2,4-dimethoxybenzyl)-1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride and propane-2-sulfonyl chloride was used in place ofcyclohexylmethanesulfonyl chloride. LCMS [M+H]⁺: 435.4. ¹H NMR (500 MHz,DMSO-d6) δ 10.45 (s, 1H), 8.67 (d, J=6.7 Hz, 1H), 8.06 (s, 1H), 7.62 (s,1H), 6.90 (d, J=7.4 Hz, 1H), 4.27 (bs, 4H), 3.74 (t, J=6.6 Hz, 2H),3.23-2.83 (m, 4H), 2.72 (t, J=6.7 Hz, 2H), 1.16 (d, J=6.8 Hz, 6H)(missing proton obscured by water peak).

Example 186. Preparation of1-(5-((4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (4 ml, 52 mmol) was added to tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate(200 mg, 0.346 mmol). The mixture was heated overnight at in a sealedvial at 85° C. The mixture was then cooled to rt and, concentrated andazeotropically dried with toluene to provide crude1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate which was used without further purification. LCMS[M+H]⁺: 329.2.

Step 2:1-(5-((4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Isobutyraldehyde (10 mg, 0.14 mmol) and triethylamine (0.014 mL, 0.10mmol) were added to a solution of1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate (30 mg, 0.068 mmol) in DCM (2 mL) and MeOH (2 mL). Thereaction mixture was stirred at rt for 10 min and then sodiumtriacetoxyborohydride (43 mg, 0.20 mmol) was added. The reaction mixturewas stirred overnight at rt and then quenched with a solution ofsaturated aqueous NaHCO₃ and extracted three times with DCM. Thecombined organic extracts were washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was dissolved in DMSO, filteredthrough a 1 micron filter and purified by reverse phase HPLC usingACN/Water/0.1% TFA. The fractions containing the product were combined,frozen and lyophilized to afford a TFA salt of1-(5-((4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(12 mg, 0.023 mmol, 33% yield). LCMS [M+H]⁺: 385.3. ¹H NMR (500 MHz,DMSO-d6) δ 10.46 (s, 1H), 8.56 (d, J=7.1 Hz, 1H), 8.05 (s, 1H), 7.50 (s,1H), 6.89 (d, J=7.1 Hz, 1H), 3.79 (t, J=6.7 Hz, 2H), 3.72-3.55 (m, 4H),3.41 (s, 4H), 3.00 (d, J=39.0 Hz, 4H), 2.79 (t, J=6.7 Hz, 2H), 2.11-1.98(m, 1H), 0.94 (d, J=6.6 Hz, 6H).

The compounds in the following table were prepared by the method ofExample 186, using the appropriate commercially available aldehyde instep 2.

Example Mass No. Structure [M + H]⁺ ¹H NMR 187

439.3 (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.56 (d, J = 7.1 Hz, 1H), 7.97(s, 1H), 7.43 (s, 1H), 6.81 (dd, J = 7.2, 1.8 Hz, 1H), 3.71 (t, J = 6.7Hz, 2H), 3.59 (s, 4H), 3.09-2.80 (m, 6H), 2.71 (t, J = 6.7 Hz, 2H), 2.37(d, J = 31.0 Hz, 2H), 1.64- 1.50 (m, 5H), 1.49-1.38 (m, 2H), 1.12 (tddd,J = 24.2, 21.4, 9.8, 6.5 Hz, 4H), 0.84 (q, J = 11.2 Hz, 2H).1-(5-((4-(2- cyclohexylethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione 188

397.3 (500 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.63 (d, J = 7.1 Hz, 1H), 8.04(s, 1H), 7.50 (s, 1H), 6.88 (dd, J = 7.2, 1.8 Hz, 1H), 3.78 (t, J = 6.7Hz, 4H), 3.35 (s, 2H), 3.14 (s, 2H), 2.99 (s, 4H), 2.79 (t, J = 6.7 Hz,2H), 2.73-2.60 (m, 1H), 2.40 (d, J = 29.5 Hz, 2H), 2.13-2.01 (m, 2H),1.95-1.84 (m, 1H), 1.84- 1.69 (m, 3H). 1-(5-((4-(cyclobutylmethyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione 189

383.4 (500 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.66 (dd, J = 7.2, 0.9 Hz,1H), 8.06 (s, 1H), 7.54 (s, 1H), 6.91 (dd, J = 7.2, 1.9 Hz, 1H),3.84-3.72 (m, 5H), 3.55 (s, 3H), 3.25-2.94 (m, 6H), 2.80 (t, J = 6.7 Hz,2H), 1.05 (dh, J = 10.5, 2.8 Hz, 1H), 0.74-0.54 (m, 2H), 0.44-0.21 (m,2H). 1-(5-((4- (cyclopropylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione 190

433.2 (500 MHz, DMSO-d6) δ 10.39 (s, 1H), 8.57 (d, J = 7.2 Hz, 1H), 7.98(s, 1H), 7.44 (s, 1H), 7.23 (d, J = 36.8 Hz, 4H), 6.82 (d, J = 7.3 Hz,1H), 4.43-4.03 (m, 6H), 3.71 (t, J = 6.7 Hz, 5H), 3.19 (s, 1H), 2.95 (s,2H), 2.71 (t, J = 6.7 Hz, 2H), 2.26 (s, 3H). 1-(5-((4-(3-methylbenzyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione 191

420.3 (500 MHz, Methanol-d4) δ 8.66 (s, 1H), 8.61 (d, J = 5.4 Hz, 1H),8.48 (d, J = 7.2 Hz, 1H), 8.23 (s, 1H), 8.01 (s, 1H), 7.74 (d, J = 6.8Hz, 1H), 7.59 (s, 1H), 6.90 (dd, J = 7.3, 1.9 Hz, 1H), 4.14 (s, 2H),3.88 (s, 2H), 3.82 (t, J = 6.7 Hz, 2H), 3.07 (s, 4H), 2.86 (s, 3H), 2.79(t, J = 6.7 Hz, 3H). 1-(5-((4-(pyridin-3- ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione

Example 192. Preparation of(S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl(S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate

To a suspension of1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(1.2 g, 2.61 mmol) in toluene (20 mL) and water (2 mL) at roomtemperature was added Cs₂CO₃ (2.55 g, 7.84 mmol), tert-butyl(S)-2-methyl-4-((trifluoro-14-boraneyl)methyl)piperazine-1-carboxylate,potassium salt (3.35 g, 10.45 mmol) [see Chem Med Chem, 2016, 11,2640-2648] and RuPhos (242 mg, 0.52 mmol), followed by Pd(OAc)₂ (59 mg,0.26 mmol). The mixture was stirred at 100° C. overnight, then cooled tort and partitioned between EtOAc and water. The organic layer wasseparated, washed with brine, dried over sodium sulfate, filtered andconcentrated. Silica gel column chromatography [eluted with 0-100%EtOAc/EtOH (3:1) in heptane] provided tert-butyl(S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate,(1.12 g, 2.61 mmol, 71% yield) as an off-white foamy solid. LCMS [M+H]⁺:593.4.

Step 2.(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate

TFA (4 mL, 2 mmol) was added to a solution of tert-butyl(S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate(1.2 g, 2.0 mmol) in DCM (12 mL) and the mixture was stirred for 2 h atrt. The reaction was then concentrated and dried azeotropically withtoluene to give crude(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate (1.2 g, 1.4 mmol) which was used without furtherpurification. LCMS [M+H]⁺: 493.2.

Step 3.(S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

To a solution of(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(100 mg, 0.20 mmol) in DCE (2 mL) was added cyclohexanecarbaldehyde (21mg, 0.20 mmol), NaBH(OAc)₃ (120 mg, 0.60 mmol), 4A MS (100 mg) and DIPEA(113 mg, 0.15 mL, 0.95 mmol). The reaction was stirred at rt for 2 h.The suspension was filtered through a pad of Celite and the filtrate wasdiluted with a solution of saturated aqueous NaHCO₃ and extracted withDCM. The organic layer was dried over Na₂SO₄, filtered and concentratedto give(S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(200 mg, 0.34 mmol, 72% purity). The crude product was used in the nextstep without any other purification. LCMS [M+H]⁺: 589.2.

Step 4:(S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 192) was prepared using the method of Example 156, step 4,wherein(S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 439.1. ¹H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.57-8.55(m, 1H), 8.00 (s, 1H), 7.43 (s, 1H), 6.88-6.86 (m, 1H), 3.76 (s, 2H),3.45-3.44 (m, 2H), 2.80-2.72 (m, 3H), 2.57 (br s, 1H), 2.47-2.40 (m,1H), 2.35-2.26 (m, 1H), 2.23-2.08 (7, 2H), 2.03-1.77 (i, 3H), 1.63 (brs, 4H), 1.42-1.39 (i, 1H), 1.30-1.02 (i, 4H), 0.92-0.91 (i, 3H),0.87-0.70 (s, 2H).

The compounds in the following table were prepared from3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride by the method of Example 192, steps 3-4 using theappropriate commercially available aldehyde in step 3.

Example Mass No. Structure [M + H]⁺ ¹H NMR 193

455.2 (400 MHz, CD₃OD) δ 8.46 (d, J = 7.2 Hz, 1H), 8.44 (s, 1H), 8.02(s, 1H), 7.51 (s, 1H), 6.99 (d, J = 4.4 Hz, H), 3.88 (t, J = 6.6 Hz,2H), 3.69-3.48 (m, 4H), 3.08 (m, 4H), 2.90-2.77 (m, 7H), 2.31 (s, 1H),2.19 (s, 1H), 1.74-1.42 (m, 3H), 1.18-1.11 (m, 6H), 0.88-0.84 (m, 1H).1-(5-((4-(((2R,6S)-2,6- dimethyltetrahydro-2H-pyran-4-yl)methyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione 194

477.2 (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.46 (d, J = 7.2 Hz, 1H),8.02 (s, 1H), 7.51 (s, 1H), 6.99 (dd, J = 7.4, 1.6 Hz, 1H), 3.89 (t, J =6.7 Hz, 2H), 3.64 (s, 2H), 2.89 (t, J = 6.8 Hz, 2H), 2.78 (s, 4H), 2.63(s, 4H), 2.23 (s, 2H), 1.96 (s, 3H), 1.76 (d, J = 12.4 Hz, 3H), 1.68 (d,J = 12.2 Hz, 3H), 1.57 (d, J = 3.0 Hz, 6H). NH proton not observed dueto solvent exchange 1-(5-((4-(((3r,5r,7r)-adamantan-1-yl)methyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione 195

423.2 (400 MHz, CD₃OD) δ 8.58 (d, J = 7.6 Hz, 1H), 8.11 (s, 1H), 7.70(s, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.34 (d, J= 1.6 Hz, 1H), 4.24 (s, 2H), 3.94- 3.91 (m, 7H), 3.23 (brs, 4H),2.91-2.88 (m, 6H). 1-(5-((4-((1-methyl-1H-pyrazol-5-yl)methyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione 196

422.8 (400 MHz, Methanol-d4) δ 8.86 (s, 1H), 8.61 (d, J = 7.2 Hz, 1H),8.13 (s, 1H), 7.80 (d, J = 1.8 Hz, 1H), 7.51 (s, 1H), 7.01 (dd, J = 7.6,1.9 Hz, 1H), 4.42 (s, 2H), 3.92 (m, 5H), 3.75 (s, 2H), 3.38 (bs, 3H),2.90 (bm, 7H). NH proton not observed due to solvent exchange1-(5-((4-((1-methyl-1H-imidazol-4- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione 197

425.8 (400 MHz, Methanol-d4) δ 9.11 (d, J = 1.9 Hz, 1H), 8.50 (d, J =7.1 Hz, 1H), 8.06 (s, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.58 (s, 1H), 6.99(dd, J = 7.1, 1.9 Hz, 1H), 4.44 (s, 2H), 3.96-3.84 (m, 4H), 3.19- 2.66(m, 8H). 2 protons not integrated due to broadening. NH proton notobserved due to solvent exchange. 1-(5-((4-(thiazol-4-ylmethyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)- dione

The compounds in the following table were prepared by the method ofExample 192, using the appropriate commercially available aldehyde instep 3.

Example Mass No. Structure [M + H]⁺ ¹H NMR 198

453.0 (400 MHz, CD₃OD): δ 8.45 (d, J = 6.8 Hz, 1H), 8.02 (s, 1H), 7.50(s, 1H), 6.99 (d, J = 6.8 Hz, 1H), 3.89 (t, J = 7.2 Hz, 2H), 3.63- 3.54(s, 2H), 2.91-2.79 (m, 6H), 3.14-3.07 (m, 2H), 2.87 (t, J = 6.8 Hz, 2H),2.48-2.16 (m, 1H), 1.86-1.47 (m, 12H), 1.21-1.14 (m, 5H), ppm. NH protonnot observed due to solvent exchange.(S)-1-(5-((4-(cycloheptylmethyl)-3- methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione 199

469.3 (400 MHz, Methanol-d4) δ 8.56 (dd, J = 7.0, 2.7 Hz, 1H), 8.09 (d,J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.00 (dd, J = 7.3, 1.8 Hz, 1H), 4.14 (s,1H), 3.91 (t, J = 6.8 Hz, 2H), 3.99-3.37 (m, 8H), 3.12 (s, 3H), 2.89 (t,J = 6.8 Hz, 2H), 2.46- 1.95 (m, 1H), 1.81-1.49 (m, 2H), 1.43 (d, J = 6.6Hz, 3H), 1.29 (s, 1H), 1.22-1.10 (m, 6H), 1.04-0.84 (m, 2H). NH protonnot observed due to solvent exchange. 1-(5-(((3S)-4-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4- yl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione 200

467.3 (400 MHz, CD₃OD) δ 8.46-8.43 (m, 2H), 8.02 (s, 1H), 7.48 (s, 1H),6.99-6.97 (m, 1H), 3.88 (t, J = 7.2 Hz, 2H), 3.64-3.62 (m, 2H),3.48-3.40 (m, 2H), 3.12-2.40 (m, 8H), 1.68-1.23 (m, 12H), 0.92 (d, J =2.4 Hz, 6H). NH proton not observed due to solvent exchange.(S)-1-(5-((4-((4,4- dimethylcyclohexyl)methyl)-3- methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)dihydropyrimidine-2,4(1H,3H)-dione

Example 201. Preparation of1-(5-(((S)-4-(((1r,4S)-4-hydroxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, steps 3-4, whereintrans-4-(benzyloxy)cyclohexane-1-carbaldehyde (see WO2020/232470, 2020,A1 which is incorporated herein by reference) was used in place ofcyclohexanecarbaldehyde. LCMS [M+H]⁺: 455.2. ¹H NMR (400 MHz,Methanol-d4) 8.44 (d, J=7.1 Hz, 1H), 8.00 (d, J=11.5 Hz, 1H), 7.38 (t,1H), 6.83 (d, J=6.2 Hz, 1H), 3.88 (t, J=6.8 Hz, 2H), 3.63-3.44 (=, 3H),2.96-2.85 (i, 6H), 2.73-2.64 (m, 2H), 2.08-1.72 (m, 7H), 1.58 (q,J=12.1, 11.1 Hz, 2H), 1.37-1.22 (m, 4H), 1.11 (q, J=12.5 Hz, 2H), NH andOH protons not observed due to solvent exchange.

The compounds in the following table were prepared from(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate by the method of Example 156, steps 3-4 using theappropriate commercially available halide, mesylate or triflate in step3.

Example Mass No. Structure [M + H]⁺ ¹H NMR 202

441.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8.01(s, 1H), 7.44 (s, 1H), 6.88 (dd, J = 7.2, 1.8 Hz, 1H), 3.81 (d, J = 11.6Hz, 2H), 3.77 (t, J = 6.7 Hz, 2H), 3.49-3.38 (m, 2H), 3.30-3.19 (m, 2H),2.78 (t, J = 6.7 Hz, 3H), 2.56 (d, J = 12.1 Hz, 2H), 2.46 (d, J = 12.2Hz, 1H), 2.36 (d, J = 12.4 Hz, 1H), 2.18 (t, J = 10.5 Hz, 2H), 1.92 (s,2H), 1.66 (d, J = 12.4 Hz, 2H), 1.51 (d, J = 13.0 Hz, 1H), 1.22- 1.00(m, 2H), 0.94 (d, J = 6.2 Hz, 3H). 203

399.4 (500 MHz, Methanol-d4) δ 8.46 (dd, J = 7.1, 0.9 Hz, 1H), 8.02 (s,1H), 7.51 (dd, J = 1.9, 1.0 Hz, 1H), 7.01 (dd, J = 7.2, 1.8 Hz, 1H),3.91 (t, J = 6.7 Hz, 2H), 3.63- 3.49 (m, 2H), 2.91 (t, J = 6.8 Hz, 3H),2.73 (dd, J = 28.7, 10.7 Hz, 2H), 2.39 (dd, J = 71.2, 21.3 Hz, 4H), 2.02(d, J = 45.3 Hz, 2H), 1.81 (s, 1H), 1.04 (d, J = 6.2 Hz, 3H), 0.93 (dd,J = 7.7, 6.6 Hz, 6H). 204

413.4 (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.62 (d, J = 7.2 Hz, 1H), 8.04(s, 1H), 7.49 (s, 1H), 6.89 (dd, J = 7.1, 1.8 Hz, 1H), 3.78 (t, J = 6.7Hz, 2H), 3.62 (s, 3H), 3.29 (s, 2H), 3.00 (s, 4H), 2.79 (t, J = 6.7 Hz,2H), 2.44- 2.18 (m, 2H), 1.72-1.40 (m, 3H), 1.29 (dd, J = 29.4, 6.4 Hz,3H), 0.92 (t, J = 6.1 Hz, 6H). 205

447.3 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.57 (dd, J = 7.2, 0.9 Hz,1H), 8.01 (s, 1H), 7.51-7.23 (m, 1H), 6.88 (dd, J = 7.2, 1.8 Hz, 1H),3.77 (t, J = 6.7 Hz, 2H), 3.49- 3.42 (m, 2H), 2.83-2.70 (m, 4H), 2.60(q, J = 14.0, 11.8 Hz, 4H), 2.37 (s, 1H), 2.32-2.12 (m, 6H), 1.91 (s,1H), 0.95 (d, J = 6.2 Hz, 3H). 206

455.4 (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.74-8.50 (m, 1H), 8.04 (s,1H), 7.49 (s, 1H), 6.89 (dd, J = 7.2, 1.8 Hz, 1H), 3.84 (dd, J = 11.0,4.1 Hz, 2H), 3.78 (t, J = 6.7 Hz, 2H), 3.64 (s, 3H), 3.50 (d, J = 11.4Hz, 1H), 3.41-3.19 (m, 4H), 3.00 (d, J = 14.8 Hz, 4H), 2.79 (t, J = 6.7Hz, 2H), 2.26 (d, J = 11.8 Hz, 1H), 1.59 (d, J = 13.9 Hz, 5H), 1.22 (dd,J = 22.3, 9.4 Hz, 5H). 207

475.2 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.57 (d, J = 7.1 Hz, 1H), 8.01(s, 1H), 7.44 (s, 1H), 6.88 (dd, J = 7.2, 1.8 Hz, 1H), 3.77 (t, J = 6.7Hz, 2H), 3.50- 3.40 (m, 2H), 2.78 (t, J = 6.7 Hz, 2H), 2.68-2.53 (m,2H), 2.50- 2.28 (m, 4H), 2.17 (dt, J = 19.9, 10.0 Hz, 2H), 2.05-1.64 (m,8H), 1.09 (dt, J = 45.2, 11.8 Hz, 2H), 0.94 (d, J = 6.1 Hz, 3H). 208

434.4 (400 MHz, DMSO-d6) δ 10.41 (br s, 1H), 8.56 (d, J = 7.2 Hz, 1H),8.48 (d, J = 1.6 Hz, 1H), 8.46-8.43 (m, 1H), 8.00 (s, 1H), 7.69 (d, J =8.0 Hz, 1H), 7.43 (s, 1H), 7.37-7.31 (m, 1H), 6.90- 6.84 (m, 1H), 3.95(d, J = 14.0 Hz, 1H), 3.78-3.74 (m, 2H), 3.52- 3.42 (m, 3H), 3.23 (d, J= 14.0 Hz, 1H), 2.79-2.75 (m, 2H), 2.64-2.55 (m, 3H), 2.17 (d, J = 8.0Hz, 2H), 2.04-1.93 (m, 1H), 1.07 (d, J = 6.0 Hz, 3H). 209

427.0 (400 MHz, Methanol-d4) δ 8.62 (d, J = 7.2 Hz, 1H), 8.15 (s, 1H),7.89 (s, 1H), 7.05 (d, J = 7.3 Hz, 1H), 4.56 (s, 2H), 4.27 (q, J = 8.1Hz, 1H), 4.14 (s, 1H), 4.05-3.74 (m, 7H), 3.74-3.50 (m, 3H), 3.50-3.20(m, 3H), 2.91 (t, J = 6.8 Hz, 2H), 2.20 (dq, J = 12.8, 6.4 Hz, 1H),2.09-1.87 (m, 2H), 1.77-1.57 (m, 1H), 1.48 (d, J = 6.6 Hz, 3H). NHproton not observed due to solvent exchange.

Example 203 (alternate synthesis). Preparation of(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 203)

Step 1.(S)-3-(2,4-dimethoxybenzyl)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To a solution of(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate (2.2 g, 3.6 mmol) in DCM (20 mL) was added Et₃N (0.51mL, 3.6 mmol) followed by isobutyraldehyde (1.31 g, 18.1 mmol). Themixture was stirred at rt for 30 min and then NaBH(OAc)₃ (3.84 g, 18.1mmol) was added. The reaction was stirred overnight at rt. The reactionwas quenched with a solution of saturated aqueous NaHCO₃ and extractedwith DCM. The organic layer was dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (eluting with 10-100%EtOAc (containing 25% EtOH) in hexane) provided(S)-3-(2,4-dimethoxybenzyl)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(1.25 g, 2.28 mmol, 63% yield) as a white solid. LCMS [M+H]⁺: 549.3.

Step 2.(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 203)

TFA (10 mL) was added to(S)-3-(2,4-dimethoxybenzyl)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(1.25 g, 2.28 mmol). The reaction mixture was stirred for 16 h at 90° C.and then concentrated. The crude material was dissolved in DCM andwashed with a solution of saturated aqueous NaHCO₃. The layers wereseparated and the aqueous layer was extracted with DCM. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (eluting with 10-100%EtOAc (containing 25% EtOH) in hexane) provided(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(800 mg, 1.97 mmol, 86% yield). LCMS [M+H]⁺: 399.4. ¹H NMR (500 MHz,Methanol-d4) δ 8.46 (dd, J=7.1, 0.9 Hz, 1H), 8.02 (s, 1H), 7.51 (dd,J=1.9, 1.0 Hz, 1H), 7.01 (dd, J=7.2, 1.8 Hz, 1H), 3.91 (t, J=6.7 Hz,2H), 3.63-3.49 (m, 2H), 2.91 (t, J=6.8 Hz, 3H), 2.73 (dd, J=28.7, 10.7Hz, 2H), 2.39 (dd, J=71.2, 21.3 Hz, 4H), 2.02 (d, J=45.3 Hz, 2H), 1.81(s, 1H), 1.04 (d, J=6.2 Hz, 3H), 0.93 (dd, J=7.7, 6.6 Hz, 6H).

Examples 210 and 211. Preparation of1-(5-(((S)-4-(((1r,4S)-4-methoxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 210) and1-(5-(((S)-4-(((1s,4R)-4-methoxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 211)

Prepared using the method of Example 202, wherein a commerciallyavailable mixture of cis and trans 1-(bromomethyl)-4-methoxycyclohexanewas used in place of trans-4-(benzyloxy)cyclohexane-1-carbaldehyde. Thestereoisomers were purified after the final step by reverse-phase HPLC(eluting with using ACN/Water/0.1% TFA).

Example 210.1-(5-(((S)-4-(((1r,4S)-4-methoxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Eluted first, minor isomer. LCMS [M+H]⁺: 469.3. ¹H NMR (400 MHz,DMSO-d6) δ 10.45 (s, 1H), 8.64 (d, J=7.2 Hz, 1H), 8.05 (s, 1H), 7.52 (s,1H), 6.90 (dd, J=7.2, 1.8 Hz, 1H), 4.99 (s, 4H), 3.79 (t, J=6.7 Hz, 2H),3.72 (s, 2H), 3.23 (s, 4H), 3.13-2.94 (m, 4H), 2.79 (t, J=6.7 Hz, 3H),2.37 (d, J=30.0 Hz, 1H), 2.00 (s, 2H), 1.92-1.57 (m, 2H), 1.26 (s, 3H),1.07 (dt, J=37.0, 13.5 Hz, 4H).

Example 211.1-(5-(((S)-4-(((1s,4R)-4-methoxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Eluted second, major isomer. LCMS [M+H]⁺: 469.3. ¹H NMR 400 MHz,DMSO-d6) δ 10.44 (s, 1H), 8.63 (d, J=7.2 Hz, 1H), 8.04 (s, 1H), 7.50 (s,1H), 6.90 (dd, J=7.2, 1.8 Hz, 1H), 3.78 (t, J=6.7 Hz, 2H), 3.67 (s, 5H),3.23 (s, 3H), 3.20 (s, 3H), 3.17-2.84 (m, 4H), 2.79 (t, J=6.7 Hz, 2H),2.46-2.21 (m, 1H), 1.92-1.69 (m, 3H), 1.55 (s, 1H), 1.51-1.29 (m, 4H),1.25 (s, 3H).

Example 212. Preparation of(S)-1-(5-((4-(cycloheptylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 186, wherein tert-butyl(S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylatewas used in place of tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate,and cyclopentanecarbaldehyde was used in place of isobutyraldehyde. LCMS[M+H]⁺: 425.3. ¹H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.63 (d, J=7.2Hz, 1H), 8.04 (s, 1H), 7.51 (s, 1H), 6.90 (dd, J=7.2, 1.9 Hz, 1H), 4.39(s, 3H), 3.78 (t, J=6.7 Hz, 2H), 3.61 (d, J=44.7 Hz, 3H), 3.30 (d,J=20.9 Hz, 2H), 3.00 (d, J=14.0 Hz, 3H), 2.79 (t, J=6.7 Hz, 2H), 2.18(s, 1H), 1.79 (d, J=20.7 Hz, 2H), 1.58 (ddd, J=38.4, 7.7, 4.0 Hz, 4H),1.42-1.10 (m, 5H).

Example 213. Preparation of(S)-1-(5-((4-(cyclobutylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 186, wherein tert-butyl(S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylatewas used in place of tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate,and cyclobutanecarbaldehyde was used in place of isobutyraldehyde. LCMS[M+H]⁺: 411.5. ¹H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.58 (d, J=7.1Hz, 1H), 8.02 (s, 1H), 7.45 (s, 1H), 6.89 (dd, J=7.1, 1.8 Hz, 1H), 3.78(t, J=6.7 Hz, 2H), 3.47 (s, 2H), 2.79 (t, J=6.7 Hz, 2H), 2.76-2.57 (m,3H), 2.56 (s, 2H), 2.14 (d, J=47.7 Hz, 3H), 1.99 (s, 3H), 1.92-1.73 (m,3H), 1.65 (s, 2H), 1.03 (d, J=50.1 Hz, 3H).

The compounds in the following table were prepared using the method ofExample 192, wherein potassium(R)-((4-(tert-butoxycarbonyl)-3-methylpiperazin-1-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-14-boraneyl)methyl)piperazine-1-carboxylate,potassium salt and the appropriate commercially available aldehyde wasused in place of cyclohexanecarbaldehyde.

Example Mass No. Structure [M + H]⁺ ¹H NMR 214

439.1 (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.60-8.54 (m, 1H), 8.00 (s,1H), 7.44 (s, 1H), 6.89-6.86 (m, 1H), 3.79-3.75 (m, 2H), 3.51- 3.39 (m,2H), 2.81-2.71 (m, 3H), 2.58- 2.52 (m, 2H), 2.45-2.39 (m, 1H), 2.36-2.26(m, 1H), 2.24-2.06 (m, 2H), 2.00-1.75 (m, 3H), 1.63 (br s, 4H),1.47-1.35 (m, 1H), 1.29-1.07 (m, 3H), 0.92 (d, J = 6.0 Hz, 3H),0.89-0.69 (m, 2H). 215

434.1 (400 MHz, CDCl₃) δ 8.55 (d, J = 1.8 Hz, 1H), 8.49-8.47 (m, 1H),8.35 (d, J = 7.2 Hz, 1H), 8.09- 7.88 (m, 2H), 7.67-7.64 (m, 1H), 7.29(s, 1H), 7.27-7.25 (m, 1H), 6.89-6.87 (m, 1H), 4.02-3.99 (m, 1H), 3.88(t, J = 6.8 Hz, 2H), 3.48 (s, 2H), 3.24-3.21 (m, 1H), 2.90 (t, J = 6.8Hz, 2H), 2.71-2.50 (m, 4H), 2.25-2.23 (m, 2H), 2.07- 2.06 (m, 1H), 1.14(d, J = 6.4 Hz, 3H). 216

399.0 (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.45 (d, J = 7.3 Hz, 1H),8.02 (s, 1H), 7.50 (s, 1H), 6.99 (dd, J = 7.2, 2.0 Hz, 1H), 4.73-4.50(m, 1H), 3.89 (t, J = 6.8 Hz, 2H), 3.63 (d, J = 13.5 Hz, 1H), 3.58 (d, J= 13.5 Hz, 1H), 3.19 (d, J = 12.0 Hz, 1H), 2.89 (t, J = 6.8 Hz, 2H),2.87- 2.71 (m, 4H), 2.65 (s, 1H), 2.53- 2.19 (m, 3H), 1.93 (hept, J =6.1 Hz, 2H), 1.18 (d, J = 6.2 Hz, 3H), 0.98 (d, J = 6.0 Hz, 3H), 0.96(s, 3H). NH proton not observed due to solvent exchange 217

441.3 (400 MHz, Methanol-d4) δ 8.53 (d, J = 7.2 Hz, 1H), 8.46 (d, J =7.2 Hz, 1H), 8.03 (s, 1H), 7.51 (s, 1H), 7.00 (dd, J = 7.2, 1.8 Hz, 1H),3.98-3.87 (m, 4H), 3.63 (d, J = 13.6 Hz, 1H), 3.58 (d, J = 13.6 Hz, 1H),3.50-3.37 (m, 2H), 3.16 (dt, J = 12.2, 3.4 Hz, 1H), 2.90 (t, J = 6.8 Hz,2H), 2.87-2.76 (m, 4H), 2.62 (t, J = 10.9 Hz, 1H), 2.45 (t, J = 10.7 Hz,1H), 2.36 (dd, J = 11.2, 4.4 Hz, 1H), 2.29-2.18 (m, 1H), 1.97-1.84 (m,1H), 1.78 (ddd, J = 13.3, 4.0, 2.1 Hz, 1H), 1.66-1.58 (m, 1H), 1.38-1.21(m, 2H), 1.17 (d, J = 6.2 Hz, 3H). NH proton not observed due to solventexchange

The compounds in the following table were prepared using the method ofExample 192, wherein potassium(R)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate[see J. Med. Chem. 2012, 55, 7796-7816] was used in place of tert-butyl(S)-2-methyl-4-((trifluoro-14-boraneyl)methyl)piperazine-1-carboxylate,potassium salt, and the appropriate commercially available aldehyde wasused in place of cyclohexanecarbaldehyde.

Example Mass No. Structure [M + H]⁺ ¹H NMR 218

439.1 (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.40 (d, J = 7.2 Hz, 1H), 7.99(s, 1H), 7.43 (s, 1H), 6.88-6.84 (m, 1H), 3.96-3.91 (m, 1H), 3.76 (t, J= 6.8 Hz, 2H), 3.19-3.15 (m, 1H), 2.77 (t, J = 6.8 Hz, 2H), 2.62- 2.51(m, 3H), 2.44 (br s, 1H), 2.19-2.09 (m, 1H), 2.07-1.95 (m, 3H),1.88-1.86 (m, 1H), 1.76- 1.56 (m, 5H), 1.50-1.37 (m, 1H, 1.25-1.03 (m,6H), 0.84- 0.75 (m, 2H). 219

441.2 (400 MHz, Methanol-d4) δ 8.63 (d, J = 7.2 Hz, 1H), 8.14 (d, J =2.2 Hz, 1H), 7.81 (d, J = 5.4 Hz, 1H), 7.05-6.94 (m, 1H), 4.89-4.88 (m,2H), 4.29-4.16 (m, 1H), 4.00- 3.85 (m, 5H), 3.84-3.66 (m, 2H), 3.66-3.55(m, 1H), 3.50-3.41 (m, 2H), 3.26-3.05 (m, 4H), 2.90 (t, J = 6.8 Hz, 2H),2.24-2.08 (m, 1H), 1.78-1.47 (m, 5H), 1.45- 1.30 (m, 3H). NH protons notobserved due to solvent exchange. 220

399.3 (400 MHz, CD₃OD) δ 8.46 (s, 1H), 8.45 (d, J = 6.8 Hz, 1H), 8.01(s, 1H), 7.50 (s, 1H), 6.99-6.96 (m, 1H), 4.18 (d, J = 14.0 Hz, 2H),3.88 (d, J = 6.8 Hz, 2H), 3.12-3.08 (m, 2H), 2.88 (t, J = 6.4 Hz, 2H),2.72-2.37 (m, 7H), 1.99-1.95 (m, 1H), 1.23 (d, J = 6.0 Hz, 3H), 0.97 (d,J = 6.4 Hz, 6H).

The compounds in the following table were prepared using the method ofExample 192, wherein potassium(S)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate[see J. Med. Chem. 2012, 55, 7796-7816] was used in place of tert-butyl(S)-2-methyl-4-((trifluoro-14-boraneyl)methyl)piperazine-1-carboxylate,potassium salt and the appropriate commercially available aldehyde wasused in place of cyclohexanecarbaldehyde.

Example Mass No. Structure [M + H]⁺ ¹H NMR 221

439.1 (400 MHz, DMSO-d6) δ = 10.43 (br s, 1H), 8.55 (d, J = 7.2 Hz, 1H),7.99 (s, 1H), 7.43 (s, 1H), 6.93-6.81 (m, 1H), 3.94 (d, J = 13.8 Hz,1H), 3.78-3.74 (m, 2H), 3.17 (d, J = 13.8 Hz, 1H), 2.78- 2.75 (m, 2H),2.63-2.52 (m, 3H), 2.47-2.41 (m, 1H), 2.19-1.96 (m, 4H), 1.87 (d, J =8.6 Hz, 1H), 1.76-1.57 (m, 5H), 1.49-1.37 (m, 1H), 1.24-1.05 (m, 6H),0.90- 0.69 (m, 2H). 222

399.0 (400 MHz, DMSO-D6) δ 10.44 (s, 1H), 8.60-8.57 (m, 1H), 8.31 (s,1H), 8.13 (s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.46 (s, 1H), 6.87-6.88 (m,1H), 4.00 (m, 1H), 3.76 (t, J = 6.4 Hz, 2H), 3.55-3.50 (m, 1H),2.92-2.08 (m, 6H), 2.32-2.10 (m, 3H), 1.85 (s, 1H), 1.13 (d, J = 6.0 Hz,3H), 0.87 (d, J = 6.4 Hz, 6H). 223

440.8 (400 MHz, Methanol-d4) δ 8.48 (d, J = 7.4 Hz, 1H), 8.04 (s, 1H),7.54 (s, 1H), 6.98 (d, J = 7.1 Hz, 1H), 4.30 (s, 1H), 4.00-3.85 (m, 4H),3.45 (t, J = 12.0 Hz, 4H), 3.16- 2.77 (m, 8H), 2.55 (s, 1H), 2.11 (s,1H), 1.69 (d, J = 13.2 Hz, 3H), 1.34 (d, J = 17.8 Hz, 5H). NH protonsnot observed due to solvent exchange. 224

411.1 (400 MHz, Methanol-d4) δ 8.46 (d, J = 7.2 Hz, 1H), 8.37 (s, 1H),8.02 (s, 1H), 7.50 (s, 1H), 6.97 (dd, J = 7.2, 1.9 Hz, 1H), 4.20 (d, J =14.3 Hz, 1H), 3.89 (t, J = 6.8 Hz, 2H), 3.32-3.20 (m, 1H), 3.08 (s, 2H),2.97-2.86 (m, 4H), 2.75 (d, J = 8.0 Hz, 3H), 2.41 (s, 1H), 2.18 (d, J =7.8 Hz, 2H), 2.02 (d, J = 7.5 Hz, 1H), 1.87 (s, 3H), 1.35-1.28 (m, 2H),1.26 (d, J = 4.9 Hz, 4H). NH protons not observed due to solventexchange. 225

427.1 (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.58 (d, J = 7.3 Hz, 1H), 8.13(s, 1H), 8.01 (s, 1H), 7.46 (s, 1H), 6.86 (d, J = 7.2 Hz, 1H), 4.06-3.94 (m, 2H), 3.82-3.71 (m, 3H), 3.63 (q, J = 8.6, 7.9 Hz, 1H), 3.10-2.85 (m, 3H), 2.77 (t, J = 6.7 Hz, 2H), 2.72-2.54 (m, 5H), 2.37- 2.19(m, 2H), 1.94 (qd, J = 12.4, 6.7 Hz, 1H), 1.86-1.72 (m, 2H), 1.46 (dq, J= 12.0, 7.8 Hz, 1H), 1.11 (d, J = 6.0 Hz, 3H). NH protons not observeddue to solvent exchange.

Example 226. Preparation of(S)-1-(5-((4-((3,3-difluorocyclobutyl)methyl)-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156 wherein potassium(S)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate[see J. Med. Chem. 2012, 55, 7796-7816] was used in place of potassium((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)trifluoroborate and(3,3-difluorocyclobutyl)methyl 4-methylbenzenesulfonate was used inplace of (bromomethyl)cyclohexane. LCMS [M+H]⁺: 447.0. ¹H NMR (400 MHz,Methanol-d4) δ 8.45 (d, J=7.1 Hz, 1H), 8.37 (s, 1H), 8.01 (s, 1H), 7.51(s, 1H), 6.98 (dd, J=7.1, 1.8 Hz, 1H), 4.19 (d, J=13.7 Hz, 1H), 3.89 (t,J=6.8 Hz, 2H), 3.34-3.27 (m, 1H), 3.07-2.94 (m, 2H), 2.89 (t, J=6.8 Hz,2H), 2.86-2.63 (m, 6H), 2.53 (t, J=11.2 Hz, 1H), 2.49-2.24 (m, 5H), 1.23(d, J=6.2 Hz, 3H), NH proton not observed due to solvent exchange.

Example 227. Preparation of(S)-1-(5-((3-ethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein potassium(S)-((4-(tert-butoxycarbonyl)-3-ethylpiperazin-1-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt and tetrahydro-2H-pyran-4-carbaldehyde was used in placeof cyclohexanecarbaldehyde. LCMS [M+H]⁺: 455.5. ¹H NMR (400 MHz,Methanol-d4) δ 8.48 (d, J=7.2 Hz, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.52(s, 1H), 7.00 (dd, J=7.3, 1.9 Hz, 1H), 3.96 (dd, J=11.5, 4.2 Hz, 2H),3.90 (t, J=6.8 Hz, 2H), 3.86-3.50 (m, 4H), 3.50-3.39 (m, 2H), 3.28-2.51(m, 9H), 1.96 (d, J=78.4 Hz, 3H), 1.75 (d, J=13.3 Hz, 2H), 1.66 (d,J=13.2 Hz, 1H), 1.49-1.31 (m, 2H), 0.96 (t, J=7.4 Hz, 3H), NH proton notobserved due to solvent exchange.

Example 228. Preparation of(S)-1-(5-((3-ethyl-4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein(S)-((4-(tert-butoxycarbonyl)-3-ethylpiperazin-1-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt and isobutyraldehyde was used in place ofcyclohexanecarbaldehyde. LCMS [M+H]⁺: 413.3. ¹H NMR (400 MHz,Methanol-d4) δ 8.48 (d, J=7.1 Hz, 1H), 8.37 (s, 1H), 8.04 (s, 1H), 7.51(s, 1H), 7.00 (d, J=7.2 Hz, 1H), 3.90 (t, J=6.6 Hz, 2H), 3.74 (d, J=13.7Hz, 1H), 3.63 (d, J=13.7 Hz, 1H), 3.48 (s, 1H), 3.23-3.01 (m, 3H), 2.89(t, J=7.0 Hz, 5H), 2.75-2.50 (m, 2H), 2.12-1.99 (m, 1H), 1.95-1.69 (m,2H), 1.05 (t, J=6.1 Hz, 6H), 0.96 (t, J=7.4 Hz, 3H), NH proton notobserved due to solvent exchange.

Example 229. Preparation of(S)-1-(5-((4-isobutyl-3-isopropylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein(S)-((4-(tert-butoxycarbonyl)-3-isopropylpiperazin-1-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt and isobutyraldehyde was used in place ofcyclohexanecarbaldehyde. LCMS [M+H]⁺: 427.5. ¹H NMR (400 MHz,Methanol-d4) δ 8.48 (d, J=7.4 Hz, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 7.53(s, 1H), 7.00 (dd, J=6.9, 1.8 Hz, 1H), 3.90 (t, J=6.8 Hz, 2H), 3.86-3.53(m, 3H), 3.41-2.95 (m, 4H), 2.89 (t, J=6.8 Hz, 2H), 2.55 (d, J=44.4 Hz,4H), 2.12 (s, 1H), 1.11-1.01 (m, 9H), 1.00 (s, 3H), NH proton notobserved due to solvent exchange.

Example 230. (Preparation of(S)-1-(5-((3-isopropyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein(S)-((4-(tert-butoxycarbonyl)-3-isopropylpiperazin-1-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt and tetrahydro-2H-pyran-4-carbaldehyde was used in placeof cyclohexanecarbaldehyde. LCMS [M+H]⁺: 469.2. ¹H NMR (400 MHz,Methanol-d4) δ 8.49 (d, J=7.2 Hz, 1H), 8.30 (s, 1H), 8.04 (s, 1H), 7.55(s, 1H), 7.00 (dd, J=7.2, 1.8 Hz, 1H), 3.95 (dd, J=11.5, 4.2 Hz, 2H),3.90 (t, J=6.8 Hz, 2H), 3.85 (d, J=13.7 Hz, 1H), 3.72 (d, J=13.6 Hz,1H), 3.53-3.38 (m, 3H), 3.18-2.92 (m, 5H), 2.89 (t, J=6.8 Hz, 2H), 2.59(t, J=10.8 Hz, 2H), 2.50 (dd, J=12.6, 10.0 Hz, 1H), 2.41-2.28 (m, 1H),2.07-1.94 (m, 1H), 1.79 (d, J=13.4 Hz, 1H), 1.65 (d, J=13.2 Hz, 1H),1.44-1.25 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.95 (d, J=6.8 Hz, 3H), NHproton not observed due to solvent exchange.

Example 231. Preparation of1-(5-((4-(cyclohexylmethyl)-3,3-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein((4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt. LCMS [M+H]⁺: 453.3. ¹H NMR (400 MHz, Methanol-d4) δ 8.52(s, 1H), 8.46 (d, J=7.2 Hz, 1H), 8.02 (s, 1H), 7.49 (s, 1H), 7.00 (dd,J=7.4, 1.7 Hz, 1H), 3.89 (t, J=6.8 Hz, 2H), 3.61 (s, 2H), 2.89 (t, J=6.8Hz, 2H), 2.99-2.32 (m, 5H), 1.92-1.59 (m, 6H), 1.42-1.15 (m, 10H), 1.04(q, J=11.4 Hz, 2H), NH proton not observed due to solvent exchange.

Example 232. Preparation of1-(5-((3,3-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein((4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt and tetrahydro-2H-pyran-4-carbaldehyde was used in placeof cyclohexanecarbaldehyde. LCMS [M+H]⁺: 455.1. ¹H NMR (300 MHz,Methanol-d4) δ 8.45 (d, J=7.2 Hz, 1H), 8.27 (s, 1H), 8.01 (s, 1H), 7.47(s, 1H), 6.98 (d, J=7.3 Hz, 1H), 3.94 (d, J=12.8 Hz, 1H), 3.88 (t, J=6.8Hz, 2H), 3.71-3.31 (m, 9H), 3.05 (s, 5H), 2.87 (t, J=6.7 Hz, 2H),2.08-1.58 (m, 3H), 1.32 (d, J=24.2 Hz, 7H). NH proton not observed dueto solvent exchange.

Example 233. Preparation of1-(5-((4-isobutyl-3,3-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein((4-(tert-butoxycarbonyl)-3,3-dimethylpiperazin-1-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt and isobutyraldehyde was used in place ofcyclohexanecarbaldehyde. LCMS [M+H]⁺: 413.3. ¹H NMR (300 MHz,Methanol-d4) δ 8.47 (d, J=7.1 Hz, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 7.00(d, J=7.1 Hz, 1H), 3.90 (t, J=6.7 Hz, 2H), 3.81-3.36 (m, 2H), 3.11 (d,J=39.0 Hz, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.83-2.42 (m, 3H), 2.01 (ddd,J=25.6, 12.6, 5.4 Hz, 2H), 1.59-1.20 (m, 8H), 1.08 (d, J=6.5 Hz, 6H).

Example 234. Preparation of1-(5-(((1R,4R)-5-(cyclohexylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein potassium(((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate.LCMS [M+H]⁺: 437.2.

Example 235. Preparation of1-(5-(((1R,4R)-5-(pyridin-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein potassium(((1R,4R)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylateand using nicotinaldehyde was used in place of cyclohexanecarbaldehyde.LCMS [M+H]⁺: 432.2. ¹H NMR (400 MHz, CD₃OD) δ 8.80 (brs, 1H), 8.60 (d,J=7.2 Hz, 1H), 8.42 (m, 1H), 8.13 (s, 1H), 7.90 (brs, 1H), 7.77 (s, 1H),7.07 (d, J=7.2 Hz, 1H), 4.49-4.44 (m, 1H), 4.32-4.20 (m, 3H), 4.08-3.87(m, 5H), 3.62-3.61 (m, 3H), 3.04-3.01 (m, 1H), 2.90 (t, J=6.8 Hz, 2H),2.31 (s, 2H), NH proton not observed due to solvent exchange.

Example 236. Preparation of1-(5-(((1S,4S)-5-(cyclohexylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein potassium(((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate.LCMS [M+H]⁺: 437.2. ¹H NMR (400 MHz, Methanol-d4) δ 8.46 (d, J=7.2 Hz,1H), 8.03 (s, 1H), 7.52 (s, 1H), 7.02 (d, J=7.4 Hz, 1H), 4.23 (s, 1H),3.97-3.86 (m, 2H), 3.83-3.54 (m, 2H), 3.28 (s, 1H), 3.19-2.95 (m, 3H),2.95-2.84 (m, 2H), 2.84-2.61 (m, 1H), 2.23 (d, J=11.7 Hz, 1H), 2.13-2.04(m, 1H), 1.91-1.69 (m, 6H), 1.59 (s, 1H), 1.42-1.20 (m, 4H), 1.15-0.95(m, 2H), NH proton not observed due to solvent exchange.

Example 237. Preparation of1-(5-(((1S,4S)-5-(pyridin-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein potassium(((1S,4S)-5-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)trifluoroboratewas used in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylateand nicotinaldehyde was used in place of cyclohexanecarbaldehyde. LCMS[M+H]⁺: 432.1. ¹H NMR (400 MHz, Methanol-d4) δ 8.83 (s, 1H), 8.75 (d,J=5.6 Hz, 1H), 8.59 (d, J=7.3 Hz, 1H), 8.52 (d, J=8.1 Hz, 1H), 8.12 (s,1H), 7.96 (t, J=6.9 Hz, 1H), 7.78 (s, 1H), 7.07 (dd, J=7.2, 1.9 Hz, 1H),4.49 (d, J=13.3 Hz, 1H), 4.33 (d, J=13.2 Hz, 1H), 4.28 (s, 1H), 4.20 (d,J=14.7 Hz, 1H), 4.05 (d, J=14.7 Hz, 1H), 3.93 (t, J=6.8 Hz, 2H), 3.84(s, 1H), 3.62 (d, J=11.8 Hz, 1H), 3.38-3.19 (m, 2H), 3.01 (dd, J=12.0,2.7 Hz, 1H), 2.89 (t, J=6.8 Hz, 2H), 2.31 (s, 2H), NH proton notobserved due to solvent exchange.

Example 238. Preparation of1-(5-(((1S,4S)-5-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.1-(5-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To a stirred solution of1-(5-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(175 mg, 0.32 mmol) [prepared in Example 236] in TFA (5 mL) was addedTfOH (0.2 mL) and the reaction mixture was stirred for for 2 h at 70° C.The reaction was concentrated under to afford crude compound. The crudecompound was dissolved in 10% MeOH in DCM and basified withAmberlyst-A21 (free base) resin and then filtered. The filtrate wasconcentrated to afford1-(5-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(150 mg, crude). LCMS [M+H]⁺: 341.3.

Step 2.1-(5-(((1S,4S)-5-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To a stirred solution of1-(5-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(130 mg, 0.38 mmol) in DCM (5 mL) was added Et₃N (0.076 mL, 0.76 mmol)and propane-2-sulfonyl chloride (0.035 mL, 0.45 mmol) at −20° C. Thereaction mixture was stirred for 2 h at 0° C. and then quenched withmethanol and concentrated to afford the crude compound. The crudecompound was purified by PREP HPLC using: Mobile Phase: A=0.1% TFA inwater, B=Acetonitrile, Column: ATLANTIS (250 mm×21.2 mm), 5.0μ, Flow: 20mL/min. the collected fraction were concentrated under reduced pressureto afford1-(5-(((1S,4S)-5-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(12 mg, 0.022 mmol, 5.8% yield) as an off-white solid. LCMS [M+H]⁺:447.2. HPLC: Rt=5.406 min. ¹H NMR (400 MHz, Methanol-d4) δ 8.63 (dd,J=7.2, 3.1 Hz, 1H), 8.15 (d, J=1.7 Hz, 1H), 7.83 (d, J=2.8 Hz, 1H), 7.07(dd, J=7.4, 2.1 Hz, 1H), 4.59 (dd, J=13.5, 7.5 Hz, 3H), 4.44 (d, J=12.3Hz, 1H), 3.95 (t, J=6.8 Hz, 2H), 3.72 (s, 2H), 3.50 (d, J=9.1 Hz, 1H),2.91 (t, J=6.8 Hz, 2H), 2.47 (d, J=12.0 Hz, 1H), 2.23 (d, J=13.0 Hz,1H), 1.49 (d, J=2.2 Hz, 2H), 1.35 (d, J=6.8 Hz, 6H), NH proton notobserved due to solvent exchange.

Example 239. Preparation of1-(5-(((1R,4R)-5-(isopropylsulfonyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from using the method of Example 238, wherein1-(5-(((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione[prepared in Example 234] was used in place of1-(5-(((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 446.8.

Example 240. Preparation of1-(5-((4-(3-methylbutan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 240)

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium trifluoro((4-(3-methylbutan-2-yl)piperazin-1-yl)methyl)boratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 399.0. ¹H NMR (400 MHz, Methanol-d4) δ 8.47 (d, J=7.1 Hz, 1H),8.39 (s, 1H), 8.03 (s, 1H), 7.52 (s, 1H), 6.99 (d, J=7.2 Hz, 1H), 3.90(t, J=6.7 Hz, 2H), 3.70 (s, 2H), 3.31 (m, 4H), 3.07 (d, J=6.5 Hz, 1H),2.89 (t, J=6.8 Hz, 2H), 2.81 (bs, 4H), 2.30-2.16 (m, 1H), 1.25 (d, J=6.7Hz, 3H), 1.04 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H).

Example 241. Preparation of1-(5-((4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassiumtrifluoro((4-(3,3,3-trifluoro-2,2-dimethylpropyl)piperazin-1-yl)methyl)boratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 453.2. ¹H NMR (400 MHz, Methanol-d4) δ 8.61 (d, J=7.0 Hz, 1H),8.13 (s, 1H), 7.75 (s, 1H), 7.00 (dd, J=7.3, 1.9 Hz, 1H), 4.35 (s, 2H),3.93 (t, J=6.8 Hz, 2H), 3.48 (d, J=12.2 Hz, 1H), 3.08 (t, J=11.8 Hz,1H), 2.98-2.67 (m, 8H), 2.55 (d, J=10.8 Hz, 2H), 1.14 (d, J=2.1 Hz, 6H).NH proton not observed due to solvent exchange.

Example 242. Preparation of1-(5-((4-(cyclohexylmethyl)-3-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium((4-(cyclohexylmethyl)-3-oxopiperazin-1-yl)methyl)trifluoroborate wasused in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 439.2. ¹H NMR (400 MHz, Methanol-d4) δ 8.50 (d, J=7.1 Hz, 1H),8.04 (s, 1H), 7.57 (s, 1H), 7.00 (dd, J=7.1, 1.8 Hz, 1H), 3.90 (t, J=6.7Hz, 2H), 3.81 (s, 2H), 3.43 (t, J=5.5 Hz, 2H), 3.38-3.31 (m, 2H), 3.25(d, J=7.2 Hz, 2H), 2.89 (t, J=6.8 Hz, 4H), 1.80-1.59 (m, 6H), 1.24 (q,J=9.3, 6.0 Hz, 3H), 0.97 (q, J=11.9 Hz, 2H), NH proton not observed dueto solvent exchange.

Example 243. Preparation of1-(5-((4-(2-cyclohexylethyl)-3-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium((4-(2-cyclohexylethyl)-3-oxopiperazin-1-yl)methyl)trifluoroborate wasused in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 452.9. ¹H NMR (400 MHz, Methanol-d4) δ 8.52 (d, J=7.2 Hz, 1H),8.06 (s, 1H), 7.62-7.58 (m, 1H), 7.00 (dd, J=7.1, 1.9 Hz, 1H), 4.01-3.78(m, 3H), 3.51-3.38 (m, 5H), 3.12-2.96 (m, 2H), 2.89 (t, J=6.8 Hz, 2H),1.83-1.60 (m, 5H), 1.46 (dt, J=9.7, 6.8 Hz, 2H), 1.37-1.15 (m, 5H), 0.96(qd, J=14.1, 12.9, 4.4 Hz, 2H), NH proton not observed due to solventexchange.

Example 244. Preparation of(R)-1-(5-((4-(cyclohexylmethyl)-3-(methoxymethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(R)-((4-(cyclohexylmethyl)-3-(methoxymethyl)piperazin-1-yl)methyl)trifluoroboratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 469.4. ¹H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.45 (s,1H), 8.02 (s, 1H), 7.49 (s, 1H), 3.89 (t, J=6.8 Hz, 2H), 3.70-3.53 (m,4H), 3.36 (s, 4H), 3.19 (s, 1H), 3.03 (dd, J=12.0, 8.2 Hz, 1H),2.97-2.82 (m, 5H), 2.67-2.47 (m, 3H), 1.90 (d, J=13.1 Hz, 1H), 1.82-1.63(m, 5H), 1.41-1.18 (m, 4H), 1.09-0.92 (m, 2H), NH proton not observeddue to solvent exchange.

Example 245. Preparation of(R)-1-(5-((4-isobutyl-3-(methoxymethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(R)-trifluoro((4-isobutyl-3-(methoxymethyl)piperazin-1-yl)methyl)boratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 429.3. ¹H NMR (400 MHz, Methanol-d4) δ 8.46 (d, J=7.1 Hz, 1H),8.42 (1H, s) 8.02 (s, 1H), 7.50 (s, 1H), 6.98 (d, J=7.1 Hz, 1H), 3.89(t, J=6.7 Hz, 2H), 3.73-3.56 (m, 4H), 3.45 (d, J=13.1 Hz, 1H), 3.37 (s,3H), 3.31 (s, 1H), 3.12-2.96 (m, 2H), 2.94-2.84 (m, 4H), 2.72 (dd,J=13.0, 5.5 Hz, 1H), 2.67-2.55 (m, 2H), 2.05 (h, J=6.8 Hz, 1H), 1.03 (d,J=6.8 Hz, 3H), 1.01 (d, J=6.8 Hz, 3H), NH proton not observed due tosolvent exchange.

Example 246. Preparation of(R)-1-(5-((4-(cyclohexylmethyl)-3-(difluoromethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(R)-((4-(cyclohexylmethyl)-3-(difluoromethyl)piperazin-1-yl)methyl)trifluoroboratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 475.4. ¹H NMR (400 MHz, Methanol-d4) δ 8.56 (d, J=7.2 Hz, 1H),8.09 (s, 1H), 7.66 (s, 1H), 7.01 (dd, J=7.4, 2.0 Hz, 1H), 6.35 (t,J=54.3 Hz, 1H), 4.12 (s, 1H), 3.92 (t, J=6.8 Hz, 2H), 3.53 (t, J=17.9Hz, 1H), 3.10 (d, J=49.1 Hz, 4H), 2.89 (t, J=6.8 Hz, 3H), 2.59 (s, 1H),2.12 (dd, J=35.5, 24.8 Hz, 1H), 1.98-1.45 (m, 7H), 1.26 (dq, J=21.1,12.4, 11.8 Hz, 4H), 1.08-0.83 (m, 2H), NH proton not observed due tosolvent exchange.

Example 247. Preparation of(R)-1-(5-((3-(difluoromethyl)-4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(R)-((3-(difluoromethyl)-4-isobutylpiperazin-1-yl)methyl)trifluoroboratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 434.7. ¹H NMR (400 MHz, Methanol-d4) δ 8.58 (d, J=7.2 Hz, 1H),8.11 (s, 1H), 7.70 (s, 1H), 7.01 (dd, J=7.1, 1.9 Hz, 1H), 6.34 (t,J=54.1 Hz, 1H), 4.23 (d, J=24.8 Hz, 2H), 3.92 (t, J=6.7 Hz, 2H), 3.38(s, 2H), 3.12 (m, 4H), 2.90 (t, J=6.7 Hz, 4H), 2.52 (s, 1H), 1.90 (s,1H), 1.04-0.84 (m, 6H), NH proton not observed due to solvent exchange.

Example 248. Preparation of1-(5-((1,4-diazepan-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, steps 1 and 4, whereinpotassium((4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)methyl)trifluoroborate wasused in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt. LCMS [M+H]⁺: 343.1. ¹H NMR (400 MHz, Methanol-d4) δ 8.56(t, J=6.8 Hz, 1H), 8.10 (d, J=4.4 Hz, 1H), 7.71 (d, J=21.5 Hz, 1H),7.14-6.99 (m, 1H), 4.27 (d, J=44.9 Hz, 2H), 3.92 (t, J=6.7 Hz, 2H), 3.68(t, J=4.7 Hz, 2H), 3.60-3.50 (m, 3H), 3.45-3.37 (m, 2H), 3.26 (s, 1H),2.89 (t, J=6.8 Hz, 2H), 2.29-2.16 (m, 2H), NH proton not observed due tosolvent exchange.

Example 249. Preparation of1-(5-((4-(cyclohexylmethyl)-1,4-diazepan-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein potassium((4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)methyl)trifluoroborate wasused in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt. LCMS [M+H]⁺: 439.2. ¹H NMR (400 MHz, Methanol-d4) δ 8.52(d, J=7.2 Hz, 1H), 8.07 (s, 1H), 7.61 (s, 1H), 7.03 (dd, J=7.3, 2.0 Hz,1H), 4.02 (s, 2H), 3.91 (t, J=6.8 Hz, 2H), 3.51 (s, 4H), 3.23 (s, 1H),3.14-3.03 (m, 5H), 2.90 (t, J=6.8 Hz, 2H), 2.25-2.10 (m, 2H), 1.87-1.66(m, 6H), 1.44-1.19 (m, 4H), 1.07 (t, J=11.7 Hz, 2H), NH proton notobserved due to solvent exchange.

Example 250. Preparation of1-(5-((4-isobutyl-1,4-diazepan-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, wherein potassium((4-(tert-butoxycarbonyl)-1,4-diazepan-1-yl)methyl)trifluoroborate wasused in place of tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt and isobutyraldehyde was used in place ofcyclohexanecarbaldehyde. LCMS [M+H]⁺: 399.3. ¹H NMR (400 MHz, CD30D) δ8.44 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.49 (s, 1H), 7.02 (d, J=6.6 Hz,1H), 3.88 (t, J=7.2 Hz, 2H), 3.73 (s, 2H), 3.14-3.07 (m, 4H), 2.90-2.69(m, 8H), 1.97 (m, 3H), 0.97 (d, J=6.6 Hz, 6H), NH proton not observeddue to solvent exchange.

Example 251. Preparation of1-(5-(((1R,5S)-8-(3-fluorobenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl(1R,5S)-3-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-3,8-diazabicyclo[3,2,1]octane-8-carboxylate

To a suspension of1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(600 mg, 1.30 mmol) in t-amyl-OH (6 mL) at rt was added Cs₂CO₃ (2.6 mL,1.5 M aqueous solution), potassium(((1R,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)trifluoroborate(518 mg, 1.56 mmol) and Ad₂n-BuP-Pd-G₃ (44 mg, 0.06 mmol) in theglove-box. The reaction mixture was stirred at 90° C. for 16 h underinert atmosphere. The reaction mixture was then filtered andconcentrated. The crude product was purified by silica gelchromatography (eluted with ethyl acetate in petroleum ether) to givetert-butyl(1R,5S)-3-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylateas a light yellow solid. LCMS [M+H]⁺: 605.2.

Step 2:1-(5-(((1R,5S)-8-(3-fluorobenzyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared.

using the method of Example 156, steps 2-4, wherein tert-butyl(1R,5S)-3-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylatewas used in place of tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylateand 1-(bromomethyl)-3-fluorobenzene was used in place of(bromomethyl)cyclohexane. LCMS [M+H]⁺: 463.1. ¹H NMR (400 MHz, DMSO-d6)5=10.43 (br s, 1H), 8.57 (d, J=7.2 Hz, 1H), 7.99 (s, 1H), 7.41 (s, 1H),7.38-7.28 (m, 1H), 7.20-7.17 (m, 2H), 7.07-6.98 (m, 1H), 6.91-6.88 (m,1H), 3.76 (t, J=6.8 Hz, 2H), 3.49-3.47 (m, 4H), 3.04 (br s, 2H), 2.76(t, J=6.8 Hz, 2H), 2.54-2.52 (m, 2H), 2.32-2.25 (m, 2H), 1.94-1.83 (m,2H), 1.81-1.71 (m, 2H).

Example 252. Preparation of1-(5-(((1R,5S)-8-(cyclohexylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 2-4, wherein tert-butyl(1R,5S)-3-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylatewas used in place of tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylate.LCMS [M+H]⁺: 451.1. ¹H NMR (400 MHz, DMSO-d6) δ 10.43 (br s, 1H), 8.56(d, J=7.1 Hz, 1H), 7.99 (s, 1H), 7.40 (s, 1H), 6.89-6.87 (m, 1H), 3.75(t, J=6.8 Hz, 2H), 3.45-3.42 (m, 2H), 3.01 (br s, 2H), 2.76 (t, J=6.8Hz, 2H), 2.48 (br s, 2H), 2.24-2.21 (m, 2H), 2.06 (d, J=7.2 Hz, 2H),1.87-1.53 (m, 9H), 1.09 (br s, 4H), 0.91-0.74 (m, 2H).

Example 253. Preparation of1-(5-(((1R,5S)-8-(pyridin-3-ylmethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, steps 2-4, wherein tert-butyl(1R,5S)-3-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylatewas used in place of tert-butyl(S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylateand nicotinaldehyde was used in place of cyclohexanecarbaldehyde. Thereductive amination was carried out with NaBH₃CN, ZnCl₂, and DIPEA inTHF/EtOH. LCMS [M+H]⁺: 446.1. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=2.0Hz, 1H), 8.50-8.48 (m, 1H), 8.35 (d, J=7.2 Hz, 1H), 7.92 (s, 1H),7.79-7.67 (m, 2H), 7.27-7.24 (m, 2H), 6.91-6.90 (m, 1H), 3.88 (t, J=6.7Hz, 2H), 3.51 (d, J=16.0 Hz, 4H), 3.10 (br s, 2H), 2.91 (t, J=6.8 Hz,2H), 2.57-2.55 (m, 2H), 2.39-2.37 (m, 2H), 1.99-1.84 (m, 4H).

Example 254. Preparation of1-(5-((4-isobutyl-2-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. 4-isobutylpiperazin-2-one

To a stirred solution of piperazin-2-one (500 mg, 4.99 mmol) in DCM (20mL) was added TEA (2.0 mL 14.97 mmol) and isopropyl aldehyde (720 mg,9.98 mmol) at rt. The mixture was stirred for 30 min and then NaBH(OAc)₃(2.1 g, 9.98 mmol) was added. The reaction was stirred at rt for 4 h andthen diluted with DCM and water. The organic layer was dried overNa₂SO₄, filtered and concentrated to afford 4-isobutylpiperazin-2-one(500 mg, crude). LCMS [M+H]⁺: 157.0.

Step 2.1-((3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl)-4-isobutylpiperazin-2-one.

To a stirred solution of 4-isobutylpiperazin-2-one (184 mg, 1.16 mmol)in THF (5 mL) at 0° C. was added NaH (88.0 mg, 2.23 mmol). The mixturewas stirred for 30 min and allowed to warm to rt. A solution of(3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl 4-methylbenzenesulfonate (500mg, 1.16 mmol) in THF (5 mL) was added and the reaction was stirred for1 h at rt. The reaction was diluted with EtOAc and water, the organiclayer was dried over Na₂SO₄, filtered and concentrated. The crudematerial was purified by silica gel chromotography (eluted with 60%EtOAc in hexanes) to afford1-((3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl)-4-isobutylpiperazin-2-one(130 mg). LCMS [M+H]⁺: 413.0.

Step 3:1-(5-((4-isobutyl-2-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared using the method of Example 1, steps 1 and 5, wherein1-((3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl)-4-isobutylpiperazin-2-onewas used in place of 5-bromo-3-iodopyrazolo[1,5-a]pyridine. LCMS [M+H]⁺:399.1. ¹H NMR (400 MHz, DMSO-d6): δ 10.45 (s, 1H), 8.60 (d, J=7.6 Hz,1H), 8.16 (brs, 2H), 8.03 (s, 1H), 7.43 (s, 1H), 6.73 (d, J=7.2 Hz, 1H),4.54 (s, 2H), 3.77 (t, J=6.4 Hz, 2H), 3.23-3.21 (m, 2H), 3.05 (s, 2H),2.77 (t, J=6.8 Hz, 2H), 2.60-2.50 (m, 2H), 2.11-2.09 (m, 2H), 1.78-1.72(m, 1H), 0.85 (d, J=6.4 Hz, 6H).

Example 255. Preparation of1-(5-((4-(cyclohexylmethyl)-2-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 254, whereincyclohexanecarbaldehyde was used in place of isopropyl aldehyde. LCMS[M+H]⁺: 439.2. ¹H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 8.60 (d, J=7.3Hz, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.43 (s, 1H), 6.73 (dd, J=7.3, 1.9Hz, 1H), 4.54 (s, 2H), 3.77 (t, J=6.7 Hz, 2H), 3.21 (t, J=5.4 Hz, 2H),3.04 (s, 2H), 2.77 (t, J=6.7 Hz, 2H), 2.58 (t, J=5.5 Hz, 2H), 2.53-2.50(m, 1H), 2.14 (d, J=7.3 Hz, 2H), 1.76-1.56 (m, 5H), 1.47 (ddt, J=10.3,6.2, 3.3 Hz, 1H), 1.29-1.07 (m, 3H), 0.82 (q, J=11.5 Hz, 2H).

Example 256. Preparation of1-(5-(((3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl(3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate

To a stirred solution of tert-butyl(3S,5R)-3,5-dimethylpiperazine-1-carboxylate (200 mg, 0.933 mmol) in DCM(5 mL) 0° C. was added tetrahydro-2H-pyran-4-carbaldehyde (159 mg, 1.39mmol) and TEA (0.39 mL, 2.79 mmol). The mixture was stirred for 30 minand then NaBH(OAc)₃ (395 mg, 1.86 mmol) was added and the mixture wasstirred for 2 h at rt. The reaction was diluted with DCM and water theorganic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude compound was purified by silica gel chromotography (eluting with10% MeOH in DCM) to obtain tert-butyl(3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate(200 mg, 0.64 mmol, 69% yield). LCMS [M+H]⁺: 313.2.

Step 2.(2S,6R)-2,6-dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperazinehydrochloride

To a stirred solution of tert-butyl(3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazine-1-carboxylate(200 mg, 0.64 mmol) in DCM (2 mL) was added 4M HCl in dioxane (2 mL) andthe mixture was stirred for 2 h at rt. The reaction was thenconcentrated to afford crude(2S,6R)-2,6-dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperazinehydrochloride (200 mg, crude) which was used without furtherpurification. LCMS [M+H]⁺: 213.2.

Step 3.5-(((3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)-3-iodopyrazolo[1,5-a]pyridine

To a stirred solution of (3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl4-methylbenzenesulfonate (200 mg, 0.467 mmol) in DMF (4.0 mL) was addedCs₂CO₃ (456 mg, 1.401 mmol). The mixture was stirred for 30 min at 0° C.and then a solution of(2S,6R)-2,6-dimethyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperazinehydrochloride (99.1 mg, 0.467 mmol) in DMF (1 mL) was added. The mixturewas stirred for 1 h at rt. The reaction was diluted with EtOAc and waterand the organic layer was dried over Na₂SO₄, filtered and concentrated.The crude compound was purified by silica gel chromotography (elutingwith 30% EtOAc in hexanes) to obtain5-(((3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)-3-iodopyrazolo[1,5-a]pyridine(80 mg, 0.17 mmol, 40% yield). LCMS [M+H]⁺: 469.0.

Step 4:1-(5-(((3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared using the method of Example 1, steps 1 and 5, wherein5-(((3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1-yl)methyl)-3-iodopyrazolo[1,5-a]pyridinewas used in place of 5-bromo-3-iodopyrazolo[1,5-a]pyridine. LCMS [M+H]⁺:455.4. ¹H NMR (400 MHz, CD₃OD): δ 8.46 (d, J=7.2 Hz, 1H), 8.02 (s, 1H),7.49 (s, 1H), 6.99-6.97 (m, 1H), 3.97-3.87 (m, 4H), 3.63 (s, 2H), 3.42(t, J=11.6 Hz, 4H), 3.05-2.98 (m, 4H), 2.88 (t, J=6.4 Hz, 2H), 2.30-2.25(m, 2H), 1.94-1.93 (m, 2H), 1.79-1.75 (m, 2H), 1.42-1.28 (m, 7H).

Example 257. Preparation of1-(5-(((3S,5R)-4-isobutyl-3,5-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 256, wherein isobutyraldehyde wasused in place of tetrahydro-2H-pyran-4-carbaldehyde. LCMS [M+H]⁺: 413.2.¹H NMR (400 MHz, Methanol-d4) δ 8.46 (d, J=7.1 Hz, 1H), 8.03 (s, 1H),7.50 (s, 1H), 6.99 (dd, J=7.1, 1.8 Hz, 1H), 3.90 (t, J=6.7 Hz, 2H), 3.60(s, 2H), 3.30-3.13 (m, 2H), 3.00-2.77 (m, 6H), 2.21 (t, J=10.7 Hz, 2H),2.00-1.85 (m, 1H), 1.26 (s, 2H), 1.25 (s, 2H), 1.05 (s, 2H), 1.04 (s,2H). NH proton not observed due to solvent exchange.

Example 258. Preparation of1-(5-(((3S,5S)-4-(cyclohexylmethyl)-3,5-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 256, wherein tert-butyl(3S,5S)-3,5-dimethylpiperazine-1-carboxylate was used in place oftert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate andcyclohexanecarbaldehyde was used in place oftetrahydro-2H-pyran-4-carbaldehyde. LCMS [M+H]⁺: 453.2. ¹H NMR (400 MHz,Methanol-d4) δ 8.51 (d, J=7.3 Hz, 1H), 8.06 (s, 1H), 7.56 (s, 1H), 7.01(d, J=7.7 Hz, 1H), 3.95-3.64 (m, 6H), 3.20-2.49 (m, 8H), 1.91-1.65 (m,6H), 1.59-1.17 (m, 9H), 1.08 (q, J=12.0 Hz, 2H). NH proton not observeddue to solvent exchange.

Example 259. Preparation of1-(5-(((3S,5S)-4-isobutyl-3,5-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 259)

Prepared using the method of Example 256, wherein tert-butyl(3S,5S)-3,5-dimethylpiperazine-1-carboxylate was used in place oftert-butyl (3S,5R)-3,5-dimethylpiperazine-1-carboxylate andisobutyraldehyde was used in place oftetrahydro-2H-pyran-4-carbaldehyde. LCMS [M+H]⁺: 413.2. ¹H NMR (400 MHz,Methanol-d4) δ 8.47 (d, J=7.3 Hz, 1H), 8.07 (s, 1H), 8.03 (s, 1H), 7.49(s, 1H), 7.00 (d, J=7.1 Hz, 1H), 3.90 (t, J=6.7 Hz, 2H), 3.82 (s, 1H),3.76-3.51 (m, 3H), 3.09 (dd, J=13.4, 9.7 Hz, 1H), 3.04-2.93 (m, 2H),2.93-2.75 (m, 3H), 2.62 (d, J=12.5 Hz, 1H), 2.46 (t, J=11.2 Hz, 1H),2.16-2.01 (m, 1H), 1.50-1.33 (m, 7H), 1.06 (t, J=6.9 Hz, 7H). NH protonnot observed due to solvent exchange.

Example 260. Preparation of(S)-1-(5-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 260)

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(S)-trifluoro((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)borate wasused in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 369.3. ¹H NMR (400 MHz, METHANOL-d4) δ 8.46 (d, J=7.2 Hz, 1H),8.03 (s, 1H), 7.52 (d, J=0.4 Hz, 1H), 7.03-7.01 (m, 1H), 3.93-3.89 (m,2H), 3.74-3.57 (m, 2H), 3.12-2.99 (m, 3H), 2.95-2.82 (m, 3H), 2.42-2.29(m, 2H), 2.25-2.19 (m, 2H), 2.05-1.95 (m, 1H), 1.91-1.78 (m, 3H),1.50-1.36 (m, 1H).

Example 261. Preparation of(R)-1-(5-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(R)-trifluoro((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)borate wasused in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 369.1. ¹H NMR (400 MHz, METHANOL-d4) 5=8.47-8.41 (m, 1H), 8.01(s, 1H), 7.50 (d, J=0.8 Hz, 1H), 7.06-6.92 (m, 1H), 3.95-3.86 (m, 2H),3.71-3.60 (m, 2H), 3.10-2.97 (m, 3H), 2.93-2.83 (m, 3H), 2.39-2.29 (m,2H), 2.21 (d, J=8.8 Hz, 2H), 2.01-1.96 (m, 1H), 1.86-1.74 (m, 3H),1.47-1.33 (m, 1H).

Example 262. Preparation of(S)-1-(5-((octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(S)-trifluoro((octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)borate wasused in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 383.1. ¹H NMR (400 MHz, Methanol-d4) δ 8.48 (d, J=7.2 Hz, 1H),8.04 (s, 1H), 7.54 (s, 1H), 6.99 (dd, J=7.2, 1.9 Hz, 1H), 4.88 (br. s,2H), 3.90 (t, J=6.8 Hz, 2H), 3.76 (s, 2H), 3.58-3.37 (m, 2H), 3.22-3.01(m, 3H), 2.89 (t, J=6.8 Hz, 2H), 2.87-2.74 (m, 2H), 2.67-2.52 (m, 2H),2.52-2.36 (m, 2H).

Example 263. Preparation of(R)-1-(5-((hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, Whereinpotassium(R)-trifluoro((hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)boratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 385.3. ¹H NMR (400 MHz, Methanol-d4) δ 8.44 (d, J=7.1 Hz, 1H),8.25 (s, 1H), 8.00 (s, 1H), 7.50 (s, 1H), 6.97 (dd, J=7.1, 1.8 Hz, 1H),3.91-3.82 (m, 3H), 3.72-3.58 (m, 4H), 3.24 (d, J=11.1 Hz, 1H), 2.98-2.71(m, 6H), 2.61-2.38 (m, 4H), 1.99 (t, J=10.9 Hz, 1H). NH proton notobserved due to solvent exchange.

Example 264. Preparation of(S)-1-(5-((hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(S)-trifluoro((hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)boratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 385.2. ¹H NMR (400 MHz, CD₃OD) δ 8.45 (d, J=7.2 Hz, 1H), 8.24(brs, 1H), 8.01 (s, 1H), 7.50 (s, 1H), 6.98 (dd, J=7.2 Hz, 1.2 Hz, 1H),3.89-3.84 (m, 3H), 3.72-3.61 (m, 4H), 3.27-3.24 (m, 1H), 2.97-2.78 (m,6H), 2.62-2.44 (m, 4H), 2.03-1.98 (m, 1H).

Example 265. Preparation of1-(5-(((2S,4R)-1-(((1r,4S)-4-methoxycyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 141, whereintrans-4-methoxycyclohexane-1-carbaldehyde was used in place of4,4-difluorocyclohexane-1-carbaldehyde. LCMS [M+H]⁺: 468.1. ¹H NMR (400MHz, CD₃OD) δ 8.55 (s, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.36(s, 1H), 6.83 (dd, J=7.1, 1.9 Hz, 1H), 3.89 (t, J=6.7 Hz, 2H), 3.62 (s,1H), 3.35 (s, 3H), 3.16 (ddd, J=15.1, 7.5, 4.4 Hz, 3H), 2.89 (t, J=6.7Hz, 4H), 2.68 (d, J=7.3 Hz, 1H), 2.25-2.07 (m, 3H), 1.96-1.56 (m, 7H),1.38-1.04 (m, 8H).

Example 266. Preparation of1-(5-((1-(((1r,4r)-4-ethoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192, steps 3-4, whereintrans-4-ethoxycyclohexane-1-carbaldehyde [see US2016/122318, 2016, A1]was used in place of cyclohexanecarbaldehyde. LCMS [M+H]⁺: 468.2. ¹H NMR(500 MHz, DMSO-d6) δ 10.45 (d, J=4.5 Hz, 1H), 8.60 (dt, J=7.1, 1.4 Hz,1H), 8.02 (d, J=1.8 Hz, 1H), 7.46-7.28 (m, 1H), 6.80 (dd, J=7.2, 1.9 Hz,1H), 3.78 (td, J=6.7, 2.8 Hz, 2H), 3.45 (p, J=6.6 Hz, 4H), 3.26-3.08 (m,2H), 2.92-2.83 (m, 3H), 2.79 (td, J=6.7, 2.0 Hz, 2H), 2.61 (d, J=6.6 Hz,2H), 1.98 (d, J=12.1 Hz, 2H), 1.92-1.65 (m, 6H), 1.49 (q, J=13.1 Hz,2H), 1.11 (s, 2H), 1.09 (t, J=7.0 Hz, 3H), 0.99 (dd, J=14.4, 11.3 Hz,2H).

Example 267. Preparation of1-(5-(1-(1-isobutylpiperidin-4-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. 5-(trimethylstannyl)pyrazolo[1,5-a]pyridine

To a stirred solution of 5-bromopyrazolo[1,5-a]pyridine (3 g, 15.2 mmol)in dioxane (40 mL) was added Pd(PPh₃)₄ (877 mg, 0.76 mmol),Hexamethylditin (4.97 g, 15.2 mmol) and the reaction was stirred for 4 hat 90° C. After completion, the reaction mixture was filtered throughcelite and concentrated to afford5-(trimethylstannyl)pyrazolo[1,5-a]pyridine (3.2 g, crude). The materialwas used without further purification. LCMS [M+H]⁺: 282.9.

Step 2. benzyl4-(pyrazolo[1,5-a]pyridine-5-carbonyl)piperidine-1-carboxylate

To a stirred solution of 5-(trimethylstannyl)pyrazolo[1,5-a]pyridine(3.0 g. 10.7 mmol) in THF (30 mL) was added benzyl4-(chlorocarbonyl)piperidine-1-carboxylate (3.0 g, 10.7 mmol) and thesolution was de-gassed by bubbling nitrogen through it for 10 min.Allylpalladium(II) chloride dimer (390 mg, 1.07 mmol) and molecularsieves (500 mg) were added and the reaction was stirred for 4 h at 60°C. After completion, the reaction mixture was concentrated. The crudecompound was purified by silica gel chromotography (eluting with 50%EtOAc in hexanes) to afford benzyl4-(pyrazolo[1,5-a]pyridine-5-carbonyl)piperidine-1-carboxylate (1.8 g,4.95 mmol, 46% yield). LCMS [M+H]⁺: 364.0.

Step 3. benzyl4-(1-(pyrazolo[1,5-a]pyridin-5-yl)vinyl)piperidine-1-carboxylate

To a stirred solution of methyl triphenylphosphonium bromide (1.47 g,4.12 mmol) in THF (10 mL) at 0° C., was slowly added 1M KOtBu (4.1 mL,4.12 mmol) resulting in a yellow color. The reaction mixture was stirredat rt for 30 min and then a solution of benzyl4-(pyrazolo[1,5-a]pyridine-5-carbonyl)piperidine-1-carboxylate (0.50 g,1.37 mmol) in THF (2 mL) was added dropwise to at 0° C. The reactionmixture was allowed to stirred at rt for 3 h. After completion, thereaction was quenched with a solution of saturated aqueous NH₄Cl and themixture was diluted with ethyl acetate and washed with water. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Thecrude compound was purified by silica gel chromotography (eluting with30% EtOAc in hexanes) to afford benzyl4-(1-(pyrazolo[1,5-a]pyridin-5-yl)vinyl)piperidine-1-carboxylate (0.21g, 0.58 mmol, 42% yield). ¹H NMR (400 MHz, CD30D) b 8.41 (d, J=7.2 Hz,1H), 7.93 (d, J=2.1 Hz, 1H), 7.45 (s, 1H), 7.36-7.30 (m, 4H), 6.76 (dd,J=7.2 Hz, 2.1 Hz, 1H), 6.49 (d, J=2.1 Hz, 1H), 5.34 (s, 1H), 5.13-5.11(m, 3H), 4.28 (s, 2H), 2.89-2.82 (m, 2H), 2.63-2.56 (m, 2H), 1.85-1.81(m, 2H), 1.43-1.40 (m, 2H).

Step 4. 5-(1-(piperidin-4-yl)ethyl)pyrazolo[1,5-a]pyridine

To a stirred solution of benzyl4-(1-(pyrazolo[1,5-a]pyridin-5-yl)vinyl)piperidine-1-carboxylate (0.20g, 0.55 mmol) in EtOH (10 mL) under a nitrogen atmosphere was added Pd/C(0.10 g). The flask was evacuated and refilled with hydrogen from aballoon and stirred for for 16 h at rt. After completion, the reactionmixture was filtered through celite and washed through with EtOH. Thefiltrate was concentrated to afford5-(1-(piperidin-4-yl)ethyl)pyrazolo[1,5-a]pyridine (0.18 g, crude). Thecompound was used in the next step without further purification.

Step 5. tert-butyl4-(1-(pyrazolo[1,5-a]pyridin-5-yl)ethyl)piperidine-1-carboxylate

To a stirred solution of5-(1-(piperidin-4-yl)ethyl)pyrazolo[1,5-a]pyridine (0.18 g, 0.78 mmol)in DCM (7 mL) at 0° C. was added Et₃N (0.33 mL, 2.4 mmol) followed bydi-tert-butyl dicarbonate (0.26 g, 1.17 mmol) and DMAP (9.59 mg, 0.078mmol). The reaction mixture was stirred at rt for 16 h. Aftercompletion, the reaction was diluted with water and extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated. The crude compound was purified by silica gelchromotography (eluting with 10-15% EtOAc in hexanes) to affordtert-butyl4-(1-(pyrazolo[1,5-a]pyridin-5-yl)ethyl)piperidine-1-carboxylate (110mg, 0.33 mmol, 42% yield). ¹H NMR (300 MHz, CD30D) δ 8.39 (d, J=7.5 Hz,1H), 7.91 (s, 1H), 6.56 (dd, J=7.2 Hz, 2.1 Hz, 1H), 6.40 (d, J=1.2 Hz,1H), 2.65-2.45 (m, 3H), 1.84-1.80 (m, 1H), 1.61-1.49 (m, 1H), 1.43-1.38(m, 10H), 1.28-1.02 (m, 6H).

Step 6. tert-butyl4-(1-(3-iodopyrazolo[1,5-a]pyridin-5-yl)ethyl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-(1-(pyrazolo[1,5-a]pyridin-5-yl)ethyl)piperidine-1-carboxylate (0.10 g0.30 mmol) in DMF (5 mL) at 0° C. was added NIS (68.2 mg, 0.30 mmol)under an inert atmosphere. The reaction mixture was stirred at rt for 3h. After completion, the reaction was quenched with water and the yellowprecipitate that formed was collected by filtration. The solid waswashed with water and dried under vacuum to afford tert-butyl4-(1-(3-iodopyrazolo[1,5-a]pyridin-5-yl)ethyl)piperidine-1-carboxylate(120 mg, 0.26 mmol, 86% yield). LCMS [M+H]⁺: 456.0.

Step 7: tert-butyl4-(1-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)ethyl)Piperidine-1-carboxylatewas prepared using the method of Example 1, step 1, wherein tert-butyl4-(1-(3-iodopyrazolo[1,5-a]pyridin-5-yl)ethyl)piperidine-1-carboxylatewas used in place of 5-bromo-3-iodopyrazolo[1,5-a]pyridine. LCMS [M+H]⁺:592.2.

Step 8:1-(5-(1-(1-isobutylpiperidin-4-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared using the method of Example 141, steps 6-8, whereintert-butyl4-(1-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)ethyl)piperidine-1-carboxylatewas used in place of tert-butyl(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylateand isobutyraldehyde was used in place of4,4-difluorocyclohexane-1-carbaldehyde. LCMS [M+H]⁺: 398.3. ¹H NMR (400MHz, Methanol-d4) b 8.51 (s, 1H), 8.43 (d, J=7.2 Hz, 1H), 8.01 (s, 1H),7.36 (s, 1H), 6.84 (dd, J=7.4, 1.9 Hz, 1H), 3.89 (t, J=6.8 Hz, 2H),3.74-3.61 (m, 1H), 3.23-3.14 (m, 2H), 2.95 (s, 1H), 2.89 (t, J=6.7 Hz,2H), 2.69 (d, J=7.2 Hz, 2H), 2.21 (s, 1H), 2.06 (d, J=19.5 Hz, 2H), 1.81(dd, J=37.0, 15.2 Hz, 7H), 1.59 (s, 1H), 1.35 (t, J=11.2 Hz, 5H).

Example 268. Preparation of1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Methanesulfonic acid (2.0 mL, 31 mmol) was added to1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione (1.24 g, 1.99 mmol)in DCM (8 mL). The resulting pale red solution was stirred overnight at40° C. The reaction mixture was quenched with 50% aqueous sodiumbicarbonate solution and extracted with 4:1dichloromethane:trifluoroethanol three times. The combined organicphases were dried over Na₂SO₄, filtered and concentrated. The crudematerial was purified by silica gel chromatography (eluting with 15-100%3:1 EtOAc:EtOH in heptane, 0.1% TEA as modifier) to afford impureproduct. The material was further purified by C18 reverse phasechromatography (eluting with 25-75% acetonitrile in water, 0.1% NH₄OH asmodifier) and the product-containing fractions were assembled and pouredinto a pH 7 phosphate buffered solution. The aqueous phase was extractedwith 4:1 dichloromethane:trifluoroethanol three times. The combinedorganic phases were concentrated in vacuo, diluted with 2:1acetonitrile:water (3 mL) and lyophilized to afford1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione(3.5 mg, 0.0072 mmol, 0.36% yield) as a white solid. LCMS [M+H]⁺: 472.3.¹H NMR (400 MHz, DMSO-d₆) δ 11.48 (s, 1H), 8.61 (d, J=7.1 Hz, 1H), 8.12(s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.33 (s, 1H), 6.85 (dd, J=7.2, 1.8 Hz,1H), 5.69 (d, J=7.8 Hz, 1H), 2.96-2.83 (m, 1H), 2.57-2.50 (m, 2H),2.46-2.35 (m, 2H), 2.17 (qd, J=12.5, 7.2 Hz, 2H), 2.02-1.90 (m, 2H),1.90-1.84 (m, 1H), 1.84-1.62 (m, 4H), 1.59-1.44 (m, 2H), 1.44-1.33 (m,2H), 1.22-1.12 (m, 1H), 1.05 (q, J=13.7, 12.7 Hz, 2H), 0.86 (d, J=6.6Hz, 3H).

Example 269. Preparation of1-(5-(azepan-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 1, steps 2 and 5, whereintert-butyl 4-methyleneazepane-1-carboxylate [see WO2021/158829, 2021,A1] was used in place of tert-butyl 4-methylenepiperidine-1-carboxylatein step 2. LCMS [M+H]⁺: 341.8. ¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H),8.41 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.36 (s, 1H), 6.84 (dd, J=7.1, 2.0Hz, 1H), 3.88 (td, J=6.8, 2.1 Hz, 2H), 3.28-3.21 (m, 2H), 3.20-3.04 (m,2H), 2.89 (td, J=6.8, 1.8 Hz, 2H), 2.75-2.61 (m, 2H), 2.09-1.89 (m, 4H),1.86-1.73 (m, 1H), 1.62 (ddt, J=18.5, 13.0, 6.5 Hz, 1H), 1.46-1.29 (m,1H). Missing NH due to solvent exchange.

Example 270. Preparation of tert-butyl4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)azepane-1-carboxylate

TEA (0.061 mL, 0.44 mmol) and di-tert-butyl dicarbonate (0.015 mL, 0.32mmol) were added to a solution of1-(5-(azepan-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 269) (100 mg, 0.21 mmol) in DCM (5 mL) at rt. The mixture wasstirred at rt for 4 h and then partioned between DCM and water. Theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and concentrated. The residue was dissolved in DMSO,filtered through a 1 micron filter and purified by reverse phase HPLCusing ACN/Water/0.1% formic acid. The fractions containing the productwere combined, frozen and lyophilized to afford tert-butyl4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)azepane-1-carboxylateas an off-white solid. LCMS [M+H-tBu]⁺: 385.9. ¹H NMR (400 MHz, CD₃OD) δ8.40 (d, J=7.1 Hz, 1H), 7.98 (d, J=2.7 Hz, 1H), 7.34 (s, 1H), 6.82 (dd,J=7.1, 1.9 Hz, 1H), 3.88 (t, J=6.7 Hz, 2H), 3.55 (dt, J=16.6, 5.4 Hz,1H), 3.37 (dd, J=15.6, 8.8 Hz, 2H), 3.25-3.12 (m, 1H), 2.89 (t, J=6.8Hz, 2H), 2.64 (d, J=7.1 Hz, 2H), 1.90-1.73 (m, 4H), 1.56 (s, 1H), 1.45(d, J=5.7 Hz, 9H), 1.40-1.19 (m, 2H). Missing NH due to solventexchange.

Example 271. Preparation of1-(5-((1-methylazepan-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(5-(azepan-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 269) using the method of Example 109, wherein paraformaldehydewas used in place of isobutyraldehyde. LCMS [M+H]⁺: 355.9. ¹H NMR (400MHz, CD₃OD) b 8.46-8.35 (m, 2H), 8.00 (s, 1H), 7.35 (s, 1H), 6.83 (dd,J=7.0, 1.9 Hz, 1H), 3.89 (t, J=6.8 Hz, 2H), 3.22 (d, J=12.2 Hz, 3H),2.94-2.83 (m, 5H), 2.74-2.60 (m, 2H), 2.09 (ddt, J=10.3, 7.2, 3.6 Hz,1H), 2.01-1.80 (m, 4H), 1.77-1.65 (m, 1H), 1.48-1.28 (m, 2H).

Example 272. Preparation of1-(5-((1-(cyclohexylmethyl)azepan-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(5-(azepan-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 269) using the method of Example 109, whereincyclohexanecarbaldehyde was used in place of isobutyraldehyde. LCMS[M+H]⁺: 438.2. ¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J=7.3 Hz, 1H), 8.38(s, 1H), 8.01 (s, 1H), 7.35 (s, 1H), 6.83 (dd, J=7.1, 1.9 Hz, 1H), 3.89(t, J=6.7 Hz, 2H), 3.41 (s, 2H), 3.22 (s, 2H), 2.98 (d, J=6.7 Hz, 2H),2.89 (t, J=6.8 Hz, 2H), 2.68 (qd, J=13.5, 7.1 Hz, 2H), 2.11-1.61 (m,12H), 1.45-1.16 (m, 4H), 1.04 (q, J=12.1 Hz, 2H).

Example 273. Preparation of1-(5-(((2S,4R)-2-methyl-1-(2,2,3,3-tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1:1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (2 mL) was added to3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(340 mg, 0.57 mmol). The reaction mixture was stirred for 16 h at 90° C.and then concentrated. The residue was taken up in DCM, stirred withbasic resin, filtered and concentrated again. The crude material wastriturated sequentially with pentane and diethyl ether to provide crude1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(360 mg) as a yellow semi solid. LCMS [M+H]⁺: 341.9.

Step 2:1-(5-(((2S,4R)-2-methyl-1-(2,2,3,3-tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To a solution of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(150 mg, 0.43 mmol) DCM (5 mL) was added triethylamine (131 mg, 1.29mmol) and 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate (137 mg,0.51 mmol). The reaction mixture was allowed to stir for 16 h at rt. Thereaction mixture was diluted with water (20 mL) and extracted with DCM(2×30 mL). The organic layer was washed with brine solution (10 mL),dried over sodium sulfate and concentrated. The crude material waspurified by reverse phase HPLC using ACN/Water/0.1% formic acid. Thefractions containing the product were combined, frozen and lyophilizedto afford1-(5-(((2S,4R)-2-methyl-1-(2,2,3,3-tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneas a white solid. LCMS [M+H]⁺: 456.1. ¹H NMR (300 MHz, CD₃OD) δ 8.40 (d,J=7.1 Hz, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.33 (s, 1H), 6.81 (dd,J=7.1, 1.9 Hz, 1H), 6.39-5.96 (m, 1H), 3.88 (t, J=6.8 Hz, 2H), 3.04 (d,J=14.0 Hz, 2H), 2.89 (t, J=6.8 Hz, 3H), 2.81-2.69 (m, 1H), 2.62 (dd,J=17.2, 5.7 Hz, 3H), 2.00 (d, J=23.6 Hz, 1H), 1.65-1.47 (m, 3H),1.35-1.27 (m, 1H), 1.02 (d, J=6.7 Hz, 3H).

Example 274. Preparation of1-(5-(((2S,4R)-1-(2,2-difluoroethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared by the method of Example 273 wherein 2,2-difluoroethyltrifluoromethanesulfonate was used in place of 2,2,3,3-tetrafluoropropyltrifluoromethanesulfonate in step 2. LCMS [M+H]⁺: 406.2. ¹H NMR (400MHz, MeOD) δ 8.41 (dd, J=7.2, 0.9 Hz, 1H), 8.17 (s, 1H), 7.99 (s, 1H),7.34 (dd, J=1.9, 1.0 Hz, 1H), 6.82 (dd, J=7.2, 1.9 Hz, 1H), 5.98 (tt,J=55.7, 4.2 Hz, 1H), 3.88 (t, J=6.8 Hz, 2H), 3.21 (d, J=6.5 Hz, 1H),3.05-2.92 (m, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.81 (dd, J=8.0, 3.4 Hz, 2H),2.64 (d, J=7.3 Hz, 2H), 2.10-1.99 (m, 1H), 1.69 (dd, J=13.5, 3.9 Hz,1H), 1.60 (dd, J=7.5, 4.2 Hz, 2H), 1.47-1.36 (m, 1H), 1.10 (d, J=6.7 Hz,3H). NH proton not observed due to solvent exchange.

Example 275. Preparation of1-(5-(((2S,4R)-2-methyl-1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared by the method of Example 273 wherein 2,2,2-trifluoroethyltrifluoromethanesulfonate was used in place of 2,2,3,3-tetrafluoropropyltrifluoromethanesulfonate in step 2. LCMS [M+H]⁺: 424.0. ¹H NMR (400MHz, MeOD) δ 8.40 (dd, J=7.2, 0.9 Hz, 1H), 7.98 (s, 1H), 7.34 (dd,J=1.9, 0.9 Hz, 1H), 6.81 (dd, J=7.2, 1.8 Hz, 1H), 3.88 (t, J=6.8 Hz,2H), 3.17-2.95 (m, 3H), 2.89 (t, J=6.8 Hz, 2H), 2.81-2.65 (m, 2H), 2.61(d, J=7.3 Hz, 2H), 1.97 (h, J=6.1 Hz, 1H), 1.66-1.49 (m, 3H), 1.34 (dtd,J=12.9, 10.7, 4.4 Hz, 1H), 1.02 (d, J=6.6 Hz, 3H). NH proton notobserved due to solvent exchange.

Example 276. Preparation of1-(5-(((2S,4R)-2-methyl-1-(3,3,3-trifluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared by the method of Example 273 wherein 3,3,3-trifluoropropyltrifluoromethanesulfonate was used in place of 2,2,3,3-tetrafluoropropyltrifluoromethanesulfonate in step 2. LCMS [M+H]⁺: 438.0. ¹H NMR (400MHz, MeOD) δ 8.42 (d, J=7.2 Hz, 1H), 7.99 (s, 1H), 7.35 (s, 1H), 6.83(dd, J=7.2, 1.9 Hz, 1H), 3.88 (t, J=6.8 Hz, 2H), 2.98 (s, 2H), 2.89 (t,J=6.8 Hz, 2H), 2.66 (d, J=7.3 Hz, 2H), 2.53 (s, 2H), 2.15-2.00 (m, 2H),1.84-1.56 (m, 4H), 1.51-1.39 (m, 2H), 1.16 (d, J=6.7 Hz, 3H). NH protonnot observed due to solvent exchange.

Example 277. Preparation of1-(5-(((2S,4R)-2-methyl-1-(oxetan-2-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneby the method of Example 109 wherein oxetane-2-carbaldehyde was used inplace of isobutyraldehyde. LCMS [M+H]⁺: 412.0. ¹H NMR (400 MHz, MeOD) δ8.44 (s, 1H), 8.42 (s, 1H), 8.01 (s, 1H), 7.36 (s, 1H), 6.86-6.79 (m,1H), 5.39-5.21 (m, 1H), 5.20-4.99 (m, 1H), 4.76-4.52 (m, 3H), 4.43-4.26(m, 2H), 3.89 (t, J=6.8 Hz, 2H), 3.63 (s, 1H), 3.23-3.00 (m, 2H), 2.89(t, J=6.8 Hz, 2H), 2.82-2.48 (m, 4H), 2.03 (d, J=6.0 Hz, 1H), 1.89-1.57(m, 2H), 1.40-1.25 (m, 3H).

Example 278. Preparation of1-(5-(((2S,4R)-1-(2,2-difluoro-3-methoxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1:1-(5-(((2S,4R)-1-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

To a mixture of3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (0.17 g, 0.32 mmol) and K₂CO₃ (0.133 g, 0.96 mmol) indioxane (5 mL) was added3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyltrifluoromethanesulfonate (0.156 g, 0.32 mmol). The reaction mixture wasstirred at 90° C. for 16 h. The reaction mixture was cooled to rt anddiluted with water and saturated aqueous NaHCO₃ solution. The mixturewas extracted with DCM and the organic layer was dried over Na₂SO₄,filtered, and concentrated to afford crude1-(5-(((2S,4R)-1-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(0.24 g) that was used without further purification. LCMS [M+H]⁺: 824.6.

Step 2:1-(5-(((2S,4R)-1-(2,2-difluoro-3-hydroxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

To a solution of1-(5-(((2S,4R)-1-(3-((tert-butyldiphenylsilyl)oxy)-2,2-difluoropropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(0.24 g, 0.29 mmol) in THF (3 mL) was added TBAF (1.0 M in THF, 2 mL)and the reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was diluted with water and extracted with DCM. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated toafford crude1-(5-(((2S,4R)-1-(2,2-difluoro-3-hydroxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(0.11 g, 0.15 mmol) as a brown solid. LCMS [M+H]⁺: 586.1.

Step 3:1-(5-(((2S,4R)-1-(2,2-difluoro-3-methoxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

To a stirred solution of1-(5-(((2S,4R)-1-(2,2-difluoro-3-hydroxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(80 mg, 0.136 mmol) in DMF (2 mL) was added sodium hydride (10 mg, 0.41mmol) at 0° C. After 5 min, methyl iodide (39 mg, 0.27 mmol) was addedand the reaction mixture was stirred at room temperature for 10 min. Thereaction mixture was diluted with water and extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andconcentrated. Silica gel column chromatography (eluting with 30% EtOAcin hexane) provided1-(5-(((2S,4R)-1-(2,2-difluoro-3-methoxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(80 mg). LCMS [M+H]⁺: 600.2.

Step 4:1-(5-(((2S,4R)-1-(2,2-difluoro-3-methoxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 278) was prepared from1-(5-(((2S,4R)-1-(2,2-difluoro-3-methoxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dioneby the method of Example 1, step 5, wherein1-(5-(((2S,4R)-1-(2,2-difluoro-3-methoxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 450.0. ¹H NMR (400 MHz, MeOD) δ 8.42-8.36 (m, 1H), 8.24 (s,1H), 7.98 (s, 1H), 7.33 (s, 1H), 6.81 (dd, J=7.3, 1.9 Hz, 1H), 3.88 (t,J=6.8 Hz, 2H), 3.65 (q, J=12.9 Hz, 2H), 3.41 (s, 3H), 2.95 (d, J=15.0Hz, 1H), 2.89 (t, J=6.8 Hz, 2H), 2.85-2.68 (m, 3H), 2.60 (d, J=7.2 Hz,2H), 2.02 (q, J=7.7 Hz, 2H), 1.61 (d, J=12.3 Hz, 2H), 1.54 (dd, J=7.7,4.0 Hz, 2H), 1.04 (d, J=6.7 Hz, 3H).

Example 279. Preparation of1-(5-(((2S,4R)-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To a solution of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (180 mg, 0.41 mmol) in THF (10 mL) was added oxetan-3-one(85 mg, 1.2 mmol), dibutyltin dichloride (62 mg, 0.20 mmol), andtriethylamine (0.2 mL, 1.2 mmol). The mixture was stirred at 80° C. for1 h and then cooled to 0° C. and phenylsilane (45 mg, 0.41 mmol) wasadded. The reaction was stirred in a capped vial at 80° C. for 4 h. Thereaction was cooled to rt, diluted with DCM and washed sequentially withwater and brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude material was purified by reverse phase HPLCusing ACN/water/0.1% formic acid. The fractions containing the productwere combined, frozen and lyophilized to afford1-(5-(((2S,4R)-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneas white solid. LCMS [M+H]⁺: 398.2. ¹H NMR (400 MHz, MeOD) δ 8.44 (dd,J=7.2, 0.9 Hz, 1H), 8.01 (s, 1H), 7.36 (d, J=1.8 Hz, 1H), 6.83 (dd,J=7.2, 1.9 Hz, 1H), 4.84-4.74 (m, 3H), 4.52 (s, 1H), 3.89 (t, J=6.8 Hz,2H), 3.81 (s, 1H), 3.24-3.02 (m, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.67 (d,J=9.1 Hz, 2H), 2.25 (d, J=19.4 Hz, 1H), 2.00-1.20 (m, 8H). NH proton notobserved due to solvent exchange.

Example 280. Preparation of1-(5-(((2S,4R)-1-cyclobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 279 wherein cyclobutanone was usedin place of oxetan-3-one. LCMS [M+H]⁺: 396.0. ¹H NMR (400 MHz, MeOD) δ8.44 (s, 1H), 8.01 (s, 1H), 7.36 (s, 1H), 6.83 (dd, J=7.2, 1.9 Hz, 1H),3.89 (t, J=6.8 Hz, 2H), 3.70 (s, 1H), 3.14 (s, 1H), 2.89 (t, J=6.8 Hz,2H), 2.68 (d, J=7.0 Hz, 2H), 2.31 (s, 2H), 2.25-2.12 (m, 3H), 1.95-1.80(m, 4H), 1.30 (s, 7H). NH proton not observed due to solvent exchange.

Example 281. Preparation of1-(5-((1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 279 wherein1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 384.1. ¹H NMR (400 MHz, MeOD) δ 8.42 (dd, J=7.1, 0.9 Hz,1H), 8.25 (s, 1H), 7.99 (s, 1H), 7.39-7.31 (m, 1H), 6.82 (dd, J=7.2, 1.9Hz, 1H), 4.75 (t, J=7.1 Hz, 2H), 4.67 (t, J=6.6 Hz, 2H), 3.88 (t, J=6.8Hz, 3H), 3.09 (d, J=11.7 Hz, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.68 (d, J=6.8Hz, 2H), 2.30 (t, J=12.1 Hz, 2H), 1.88-1.78 (m, 3H), 1.45 (td, J=14.3,7.4 Hz, 2H).

Example 282. Preparation of1-(5-((1-cyclobutylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 279 wherein1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneand cyclobutanone was used in place of oxetan-3-one. LCMS [M+H]⁺: 382.0.¹H NMR (400 MHz, MeOD) δ 8.43 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.37 (s,1H), 6.83 (dd, J=7.2, 1.8 Hz, 1H), 3.88 (t, J=6.8 Hz, 2H), 3.59 (s, 1H),3.41 (d, J=12.2 Hz, 2H), 3.35 (s, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.78-2.65(m, 3H), 2.36-2.26 (m, 2H), 2.17 (d, J=13.8 Hz, 2H), 2.04-1.79 (m, 4H),1.49 (d, J=13.3 Hz, 2H). NH proton not observed due to solvent exchange.

Example 283. Preparation of1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1:3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Triethylamine (0.066 mL, 0.47 mmol) and ethylsulfonyl chloride (37 mg,0.28 mmol) were added to a solution of3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (50 mg, 0.095 mmol) in DCM (2 mL) at 0° C. The mixture wasstirred at rt for 2 h, then diluted with DCM and washed with brine. Theorganic layer was dried over sodium sulfate, filtered and concentratedto give crude3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione,which was used without further purification. LCMS [M+H]⁺: 584.4.

Step 2:1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 283) was prepared from3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneby the method of Example 1, step 5, wherein3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 434.1. ¹H NMR (500 MHz, DMSO) δ 10.44 (s, 1H), 8.57 (dd,J=7.1, 0.9 Hz, 1H), 7.99 (s, 1H), 7.37 (dd, J=1.9, 0.9 Hz, 1H), 6.81(dd, J=7.2, 1.9 Hz, 1H), 4.12-4.00 (m, 1H), 3.77 (t, J=6.7 Hz, 2H),3.61-3.45 (m, 1H), 3.15-2.92 (m, 3H), 2.79 (t, J=6.7 Hz, 2H), 2.54 (d,J=7.4 Hz, 2H), 2.03 (dd, J=7.6, 3.9 Hz, 1H), 1.65-1.49 (m, 2H), 1.37(td, J=12.9, 5.4 Hz, 1H), 1.25-1.15 (m, 6H), 1.11 (td, J=12.6, 4.6 Hz,1H).

The compounds in the following table were prepared by the method ofExample 283, using the appropriate commercially available sulfonylchloride in step 1.

Example Mass No. Structure [M + H]⁺ ¹H NMR 284

420.1 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.57 (dd, J = 7.1, 0.9 Hz,1H), 8.00 (s, 1H), 7.36 (dd, J = 1.9, 0.9 Hz, 1H), 6.81 (dd, J = 7.1,1.9 Hz, 1H), 4.10 (t, J = 6.6 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H),3.58-3.49 (m, 1H), 2.98 (td, J = 3.2, 2.7 Hz, 1H), 2.91 (s, 3H), 2.79(t, J = 6.7 Hz, 2H), 2.57-2.53 (m, 2H), 2.10- 1.94 (m, 1H), 1.60 (d, J =13.0 Hz, 1H), 1.55-1.48 (m, 1H), 1.40 (td, J = 12.9, 5.3 Hz, 1H),1.27-1.06 (m, 4H). 285

448.2 (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.57 (d, J = 7.1 Hz, 1H), 7.99(s, 1H), 7.37 (s, 1H), 6.81 (dd, J = 7.1, 1.8 Hz, 1H), 4.12-3.99 (m,1H), 3.77 (t, J = 6.7 Hz, 2H), 3.00 (ddp, J = 21.1, 14.8, 6.7 Hz, 2H),2.79 (t, J = 6.7 Hz, 2H), 2.00 (d, J = 22.1 Hz, 2H), 1.71-1.47 (m, 4H),1.37 (td, J = 12.7, 5.3 Hz, 2H), 1.26-1.07 (m, 5H), 0.98 (t, J = 7.4 Hz,4H). 286

446.1 (400 MHz, MeOD) δ 8.41 (dd, J = 7.2, 0.9 Hz, 1H), 7.99 (s, 1H),7.35 (dd, J = 1.9, 0.9 Hz, 1H), 6.83 (dd, J = 7.2, 1.8 Hz, 1H), 4.20 (t,J = 7.0 Hz, 1H), 3.88 (t, J = 6.8 Hz, 2H), 3.70-3.60 (m, 1H), 3.13 (td,J = 13.3, 2.7 Hz, 1H), 2.89 (t, J = 6.8 Hz, 2H), 2.61 (d, J = 7.1 Hz,2H), 2.53-2.37 (m, 1H), 2.21-2.05 (m, 1H), 1.75-1.59 (m, 2H), 1.51 (td,J = 12.8, 5.3 Hz, 1H), 1.33-1.23 (m, 4H), 1.07-0.96 (m, 4H). Missing NHdue to solvent exchange.

Example 287. Preparation of1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1:1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

HATU (43 mg, 0.11 mmol) and cyclopropanecarboxylic acid (6.5 mg, 0.076mmol) were added to a solution of3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (40 mg, 0.076 mmol) in DMF (1 mL) at rt. The mixture wasstirred at rt for 5 min and then DIPEA (0.040 mL, 0.23 mmol) was added.The mixture was stirred at rt for 12 h and then diluted with ethylacetate and washed sequentially with brine. The organic layer was driedover sodium sulfate, filtered and concentrated to give crude1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione,which was used without further purification. LCMS [M+H]⁺: 560.4.

Step 2:1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 287) was prepared from1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dioneusing the method of Example 1, step 5, wherein1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 410.2. ¹H NMR (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.56 (d,J=7.1 Hz, 1H), 7.99 (s, 1H), 7.36 (s, 1H), 6.81 (dd, J=7.2, 1.8 Hz, 1H),4.85-4.48 (m, 1H), 4.19 (dd, J=89.0, 13.8 Hz, 1H), 3.77 (t, J=6.7 Hz,2H), 3.22-3.04 (m, 1H), 2.79 (t, J=6.7 Hz, 2H), 2.67-2.54 (m, 2H), 2.09(d, J=11.9 Hz, 1H), 1.93 (ddt, J=16.7, 13.1, 5.8 Hz, 1H), 1.71-1.47 (m,2H), 1.43-0.92 (m, 5H), 0.82-0.58 (m, 4H).

The compounds in the following table were prepared by the method ofExample 287, using the appropriate commercially available carboxylicacid in step 1.

Example Mass No. Structure [M + H]⁺ ¹H NMR 288

412.2 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.55 (d, J = 7.1 Hz, 1H), 7.99(s, 1H), 7.35 (s, 1H), 6.81 (dd, J = 7.1, 1.8 Hz, 1H), 4.79- 4.73 (m,1H), 4.37-4.30 (m, 1H), 4.28 (t, J = 6.4 Hz, 1H), 3.77 (d, J = 6.7 Hz,2H), 3.06 (td, J = 13.5, 2.7 Hz, 1H), 2.80 (dt, J = 10.8, 6.7 Hz, 3H),2.71-2.54 (m, 1H), 2.08 (d, J = 5.6 Hz, 1H), 1.72-1.47 (m, 2H),1.34-1.18 (m, 1H), 1.17 (d, J = 6.8 Hz, 1H), 1.10-0.92 (m, 9H). 289

424.4 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.55 (d, J = 7.1 Hz, 1H), 7.99(s, 1H), 7.34 (s, 1H), 6.80 (dd, J = 7.1, 1.8 Hz, 1H), 4.77- 4.64 (m,1H), 4.28 (d, J = 13.6 Hz, 1H), 4.07-3.98 (m, 1H), 3.76 (t, J = 6.7 Hz,2H), 3.28 (dt, J = 18.1, 8.7 Hz, 1H), 2.78 (t, J = 6.7 Hz, 2H),2.69-2.57 (m, 1H), 2.24-1.96 (m, 5H), 1.88 (dq, J = 10.8, 8.8 Hz, 1H),1.79- 1.66 (m, 1H), 1.60 (d, J = 12.9 Hz, 1H), 1.51 (d, J = 12.2 Hz,1H), 1.22 (dtd, J = 18.4, 12.8, 5.4 Hz, 1H), 1.12 (d, J = 6.8 Hz, 2H),1.06-0.87 (m, 3H). 290

467.1 (500 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.56 (d, J = 7.1 Hz, 1H), 8.00(s, 1H), 7.34 (s, 1H), 6.80 (dt, J = 7.3, 1.9 Hz, 1H), 4.92- 4.55 (m,1H), 4.31 (d, J = 13.2 Hz, 1H), 3.77 (t, J = 6.7 Hz, 2H), 3.18-3.04 (m,1H), 3.05-1.90 (m, 2H), 2.84 (dt, J = 8.0, 3.9 Hz, 1H), 2.79 (t, J = 6.7Hz, 2H), 2.75 (d, J = 4.5 Hz, 3H), 2.71- 2.57 (m, 1H), 2.08 (s, 1H),1.97- 1.49 (m, 6H), 1.38-1.17 (m, 2H), 1.16-0.86 (m, 3H). 3 missingprotons attributed to overlap with solvent peak.

Example 291. Preparation of1-(5-(((2S,4R)-2-methyl-1-(pyrrolidin-1-ylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Triethylamine (89 mg, 0.87 mmol) and pyrrolidine-1-sulfonyl chloride (60mg, 0.35 mmol) were added to a solution of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(100 mg, 0.29 mmol) in DCM (4 mL) at rt. The mixture was stirred at rtfor 16 h, then diluted with saturated aqueous NaHCO₃ solution. Themixture was extracted with DCM and the organic layer was washed withbrine. The organic layer was dried over sodium sulfate, filtered andconcentrated. The crude material was purified by reverse phase HPLCusing ACN/water/0.1% formic acid. The fractions containing the productwere combined, frozen and lyophilized to afford1-(5-(((2S,4R)-2-methyl-1-(pyrrolidin-1-ylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneas white solid. LCMS [M+H]⁺: 475.2. ¹H NMR (400 MHz, MeOD) δ 8.41 (dd,J=7.2, 0.9 Hz, 1H), 7.98 (s, 1H), 7.37-7.32 (m, 1H), 6.83 (dd, J=7.2,1.9 Hz, 1H), 4.10 (t, J=6.4 Hz, 1H), 3.88 (t, J=6.7 Hz, 2H), 3.52 (dt,J=13.2, 3.6 Hz, 1H), 3.24-3.18 (m, 4H), 3.05 (td, J=13.2, 2.7 Hz, 1H),2.89 (t, J=6.8 Hz, 2H), 2.60 (d, J=7.1 Hz, 2H), 2.07 (ddd, J=11.9, 7.7,4.0 Hz, 1H), 1.94-1.87 (m, 4H), 1.72-1.57 (m, 2H), 1.49 (td, J=12.7, 5.2Hz, 1H), 1.23 (d, J=7.0 Hz, 4H). NH proton not observed due to solventexchange.

The compounds in the following table were prepared by the method ofExample 291, using the appropriate commercially available sulfamoylchloride, carbamic chloride or isocyanate.

Example Mass No. Structure [M + H]⁺ ¹H NMR 292

449.1 (400 MHz, MeOD) δ 8.41 (dd, J = 7.2, 0.9 Hz, 1H), 7.98 (s, 1H),7.35 (dd, J = 1.9, 1.0 Hz, 1H), 6.83 (dd, J = 7.2, 1.9 Hz, 1H), 4.06 (t,J = 6.6 Hz, 1H), 3.88 (t, J = 6.8 Hz, 2H), 3.50 (d, J = 13.7 Hz, 1H),3.06 (td, J = 13.2, 2.7 Hz, 1H), 2.89 (t, J = 6.8 Hz, 2H), 2.74 (s, 6H),2.61 (d, J = 7.2 Hz, 2H), 2.13- 2.00 (m, 1H), 1.72-1.45 (m, 3H), 1.27(d, J = 4.6 Hz, 1H), 1.23 (d, J = 7.0 Hz, 3H). NH proton not observeddue to solvent exchange. 293

489.4 (400 MHz, MeOD) δ 8.41 (d, J = 7.2 Hz, 1H), 7.98 (s, 1H), 7.35 (s,1H), 6.83 (dd, J = 7.2, 1.9 Hz, 1H), 4.10 (d, J = 6.4 Hz, 1H), 3.88 (t,J = 6.8 Hz, 2H), 3.55-3.46 (m, 2H), 3.05-2.95 (m, 1H), 2.89 (t, J = 6.8Hz, 2H), 2.60 (d, J = 7.1 Hz, 2H), 2.06 (d, J = 17.9 Hz, 1H), 1.88 (t, J= 6.2 Hz, 2H), 1.74- 1.47 (m, 9H), 1.27 (s, 1H), 1.23 (d, J = 6.9 Hz,3H). Two NH protons not observed due to solvent exchange. 294

413.3 (400 MHz, MeOD) δ 8.41 (dd, J = 7.2, 0.9 Hz, 1H), 7.98 (s, 1H),7.34 (dd, J = 1.9, 0.9 Hz, 1H), 6.83 (dd, J = 7.2, 1.9 Hz, 1H),4.10-4.00 (m, 1H), 3.88 (t, J = 6.8 Hz, 2H), 3.44 (dt, J = 13.6, 3.7 Hz,1H), 3.03 (td, J = 13.3, 2.7 Hz, 1H), 2.89 (t, J = 6.8 Hz, 2H), 2.80 (s,6H), 2.59 (d, J = 7.1 Hz, 2H), 2.11 (dtd, J = 15.6, 8.1, 4.0 Hz, 1H),1.66 (dt, J = 12.6, 3.1 Hz, 1H), 1.58 (ddt, J = 13.2, 4.0, 2.0 Hz, 1H),1.43 (td, J = 12.8, 5.2 Hz, 1H), 1.28-1.20 (m, 1H), 1.18 (d, J = 7.0 Hz,3H). NH proton not observed due to solvent exchange. 295

439.3 (400 MHz, MeOD) δ 8.41 (dd, J = 7.2, 0.9 Hz, 1H), 7.98 (s, 1H),7.34 (dd, J = 1.9, 1.0 Hz, 1H), 6.83 (dd, J = 7.2, 1.9 Hz, 1H),4.17-4.09 (m, 1H), 3.88 (t, J = 6.8 Hz, 2H), 3.60-3.50 (m, 1H),3.36-3.33 (m, 4H), 3.00 (td, J = 13.3, 2.7 Hz, 1H), 2.89 (t, J = 6.8 Hz,2H), 2.59 (d, J = 7.2 Hz, 2H), 2.12 (ddd, J = 11.8, 7.9, 4.1 Hz, 1H),1.84 (h, J = 3.4 Hz, 4H), 1.70-1.54 (m, 2H), 1.41 (td, J = 12.9, 5.3 Hz,1H), 1.19 (d, J = 7.0 Hz, 4H). Missing NH due to solvent exchange. 296

453.3 (400 MHz, MeOD) δ 8.41 (dd, J = 7.2, 0.9 Hz, 1H), 7.98 (s, 1H),7.40- 7.25 (m, 1H), 6.83 (dd, J = 7.2, 1.9 Hz, 1H), 4.36 (t, J = 6.7 Hz,1H), 4.01 (p, J = 7.2 Hz, 1H), 3.92- 3.79 (m, 3H), 2.94-2.83 (m, 3H),2.59 (d, J = 7.1 Hz, 2H), 2.15- 2.03 (m, 1H), 1.90 (p, J = 6.3 Hz, 2H),1.77-1.51 (m, 6H), 1.52- 1.26 (m, 4H), 1.23-1.06 (m, 4H). Missing NH dueto solvent exchange.

Example 297. Preparation of1-(5-((1-(pyrrolidin-1-ylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 291 wherein1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 461.3. ¹H NMR (400 MHz, MeOD) δ 8.40 (dd, J=7.2, 0.9 Hz,1H), 7.98 (s, 1H), 7.36 (dd, J=1.9, 1.0 Hz, 1H), 6.82 (dd, J=7.2, 1.9Hz, 1H), 3.88 (t, J=6.8 Hz, 2H), 3.66 (d, J=12.1 Hz, 2H), 3.29-3.24 (m,3H), 2.89 (t, J=6.8 Hz, 2H), 2.77 (td, J=12.3, 2.4 Hz, 2H), 2.65 (d,J=7.0 Hz, 2H), 1.93-1.87 (m, 4H), 1.74 (d, J=13.9 Hz, 3H), 1.40-1.27 (m,3H). NH proton not observed due to solvent exchange.

Example 298. Preparation ofN-cyclopentyl-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperidine-1-sulfonamide

Prepared using the method of Example 291 wherein cyclopentylsulfamoylchloride was used in place of pyrrolidine-1-sulfonyl chloride and1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 475.3. ¹H NMR (400 MHz, MeOD) δ 8.41 (dd, J=7.1, 0.9 Hz,1H), 7.99 (s, 1H), 7.39-7.31 (m, 1H), 6.83 (dd, J=7.2, 1.9 Hz, 1H), 3.88(t, J=6.7 Hz, 2H), 3.67-3.56 (m, 3H), 2.89 (t, J=6.7 Hz, 2H), 2.71-2.61(m, 3H), 1.90 (q, J=5.5 Hz, 2H), 1.78-1.66 (m, 4H), 1.61-1.46 (m, 5H),1.32 (dd, J=18.1, 6.0 Hz, 4H). NH proton not observed due to solventexchange.

Example 299. Preparation of(2S,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N-ethyl-N,2-dimethylpiperidine-1-carboxamide

Step 1:(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N-ethyl-N,2-dimethylpiperidine-1-carboxamide

Triethylamine (74 mg, 0.73 mmol) and triphosgene (213 mg, 0.73 mmol)were added to a solution of3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(120 mg, 0.24 mmol) in DCM (5 mL) at rt. The mixture was stirred at rtfor 10 min, then N-methylethanamine (22 mg, 0.36 mmol) was added. Thereaction was stirred at rt for 4 h then diluted with water and extractedwith EtOAc. The organic layer was dried over sodium sulfate, filteredand concentrated. The crude product was purified by flash silica gelchromatography (eluted with 6.5% MeOH/DCM) to give(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N-ethyl-N,2-dimethylpiperidine-1-carboxamide(0.10 g, 0.17 mmol, 71% yield) as an off-white solid. LCMS [M+H]⁺:576.9.

Step 2:(2S,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N-ethyl-N,2-dimethylpiperidine-1-carboxamide(Example 299) was prepared from(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N-ethyl-N,2-dimethylpiperidine-1-carboxamideby the method of Example 1, step 5, wherein(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N-ethyl-N,2-dimethylpiperidine-1-carboxamidewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 427.2. ¹H NMR (400 MHz, MeOD) δ 8.41 (dd, J=7.2, 0.9 Hz,1H), 7.98 (s, 1H), 7.34 (d, J=1.6 Hz, 1H), 6.83 (dd, J=7.2, 1.9 Hz, 1H),4.03 (t, J=6.5 Hz, 1H), 3.88 (t, J=6.8 Hz, 2H), 3.42 (d, J=13.8 Hz, 1H),3.24-3.10 (m, 3H), 3.03 (td, J=13.2, 2.7 Hz, 1H), 2.89 (t, J=6.8 Hz,2H), 2.79 (s, 3H), 2.59 (d, J=7.2 Hz, 2H), 2.11 (s, 1H), 1.62 (dd,J=29.5, 13.2 Hz, 2H), 1.49-1.39 (m, 1H), 1.17 (d, J=6.9 Hz, 3H), 1.13(t, J=7.1 Hz, 3H). NH proton not observed due to solvent exchange.

Example 300. Preparation of1-(5-((1-(((1s,3s)-3-methoxycyclobutyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 112 whereincis-3-methoxycyclobutane-1-carbaldehyde was used in place of2-cyclohexyl-2,2-difluoroacetaldehyde in step 1. LCMS [M+H]⁺: 426.2. ¹HNMR (400 MHz, cd3od) δ 8.42 (d, J=7.2 Hz, 1H), 8.00 (s, 1H), 7.36 (s,1H), 6.82 (dd, J=7.4, 1.8 Hz, 1H), 3.88 (t, J=6.8 Hz, 2H), 3.79 (p,J=7.3 Hz, 1H), 3.22 (d, J=4.2 Hz, 3H), 2.89 (t, J=6.8 Hz, 4H), 2.67 (d,J=6.7 Hz, 4H), 2.56-2.44 (m, 2H), 2.24-2.03 (m, 2H), 1.85 (d, J=14.0 Hz,3H), 1.63 (dt, J=11.7, 9.2 Hz, 2H), 1.46 (d, J=13.0 Hz, 2H), 1.30 (s,1H). NH proton not observed due to solvent exchange.

Example 301. Preparation of1-(5-((1-(((1r,3R,4S)-3,4-difluorocyclopentyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 112 wherein(1r,3R,4S)-3,4-difluorocyclopentane-1-carbaldehyde was used in place of2-cyclohexyl-2,2-difluoroacetaldehyde in step 1. LCMS [M+H]⁺: 446.3. ¹HNMR (400 MHz, MeOD) δ 8.43 (dd, J=7.2, 0.9 Hz, 1H), 8.01 (s, 1H), 7.36(dd, J=1.9, 0.9 Hz, 1H), 6.83 (dd, J=7.2, 1.9 Hz, 1H), 3.89 (t, J=6.8Hz, 2H), 3.50-3.40 (m, 2H), 3.06 (d, J=7.2 Hz, 2H), 2.89 (t, J=6.8 Hz,2H), 2.85-2.75 (m, 2H), 2.70 (d, J=6.8 Hz, 2H), 2.43 (dq, J=15.2, 7.9Hz, 1H), 2.37-2.19 (m, 2H), 1.91 (d, J=14.4 Hz, 3H), 1.75 (ddq, J=26.1,12.6, 6.0 Hz, 2H), 1.53 (q, J=13.1 Hz, 2H), 1.27 (d, J=24.2 Hz, 2H). NHproton not observed due to solvent exchange.

Example 302. Preparation of1-(5-(((2S,4R)-1-(((1r,3S)-3-methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 141 whereintrans-3-methoxycyclobutane-1-carbaldehyde was used in place of4,4-difluorocyclohexane-1-carbaldehyde in step 7. LCMS [M+H]⁺: 440.3. ¹HNMR (400 MHz, cd3od) δ 8.43 (d, J=7.3 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H),7.37 (d, J=7.3 Hz, 1H), 6.87-6.78 (m, 1H), 4.05-3.65 (m, 4H), 3.63-3.36(m, 1H), 3.26-3.07 (m, 6H), 2.89 (t, J=6.7 Hz, 2H), 2.80-2.47 (m, 4H),2.19 (d, J=8.3 Hz, 3H), 1.95-1.65 (m, 4H), 1.38 (ddd, J=34.9, 6.8, 4.2Hz, 4H). Missing NH due to solvent exchange.

Example 303. Preparation of1-(5-(((2S,4R)-1-(((1s,3R)-3-methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 141 whereincis-3-methoxycyclobutane-1-carbaldehyde was used in place of4,4-difluorocyclohexane-1-carbaldehyde in step 7. LCMS [M+H]⁺: 440.4. ¹HNMR (400 MHz, cd3od) δ 8.43 (dd, J=7.4, 1.8 Hz, 1H), 8.01 (d, J=1.6 Hz,1H), 7.36 (s, 1H), 6.83 (dd, J=7.1, 1.9 Hz, 1H), 3.89 (td, J=6.8, 3.4Hz, 2H), 3.75-3.67 (m, 1H), 3.26-3.21 (m, 4H), 3.19-3.06 (m, 3H), 2.89(t, J=6.8 Hz, 2H), 2.66 (d, J=7.1 Hz, 2H), 2.60-2.47 (m, 2H), 2.30-2.12(m, 3H), 1.87 (q, J=14.0 Hz, 2H), 1.70 (dddt, J=17.3, 12.0, 9.0, 3.6 Hz,3H), 1.50 (dd, J=12.9, 5.0 Hz, 1H), 1.33 (dd, J=7.0, 3.5 Hz, 3H). NHproton not observed due to solvent exchange.

Example 304. Preparation of1-(5-(((2S,4R)-1-(((1r,3R,4S)-3,4-difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 141 wherein(1r,3R,4S)-3,4-difluorocyclopentane-1-carbaldehyde was used in place of4,4-difluorocyclohexane-1-carbaldehyde in step 7. LCMS [M+H]⁺: 460.3. ¹HNMR (400 MHz, MeOD) δ 8.49 (s, 1H), 8.43 (dd, J=7.2, 0.9 Hz, 1H), 8.01(s, 1H), 7.36 (dd, J=1.9, 0.9 Hz, 1H), 6.83 (dd, J=7.2, 1.9 Hz, 1H),5.14-4.93 (m, 1H), 3.89 (t, J=6.8 Hz, 2H), 3.64 (s, 1H), 3.22-3.00 (m,4H), 2.89 (t, J=6.8 Hz, 2H), 2.69 (d, J=7.2 Hz, 1H), 2.46-2.15 (m, 4H),1.93-1.64 (m, 5H), 1.58 (s, 1H), 1.32 (q, J=6.3 Hz, 5H).

Example 305. Preparation of1-(5-(((2S,4R)-2-methyl-1-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 141 wherein(1r,4r)-4-(trifluoromethyl)cyclohexane-1-carbaldehyde was used in placeof 4,4-difluorocyclohexane-1-carbaldehyde in step 7. LCMS [M+H]⁺: 506.4.¹H NMR (300 MHz, cd3od) δ 8.44 (d, J=7.1 Hz, 1H), 8.02 (s, 1H), 7.37 (s,1H), 6.84 (d, J=6.9 Hz, 1H), 3.89 (t, J=6.7 Hz, 2H), 3.74 (s, 1H), 2.98(s, 2H), 2.89 (t, J=6.7 Hz, 2H), 2.70 (d, J=7.1 Hz, 2H), 2.25-2.13 (m,2H), 2.05-1.75 (m, 8H), 1.49-1.26 (m, 8H), 1.14 (d, J=12.7 Hz, 2H). NHproton not observed due to solvent exchange.

Example 306. Preparation of1-(5-(((2S,4R)-1-(((R)-3,3-difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 141 wherein(R)-3,3-difluorocyclopentane-1-carbaldehyde was used in place of4,4-difluorocyclohexane-1-carbaldehyde in step 7. LCMS [M+H]⁺: 460.3. ¹HNMR (400 MHz, MeOD) δ 8.44 (d, J=7.1 Hz, 1H), 8.01 (s, 1H), 7.36 (d,J=2.3 Hz, 1H), 6.84 (ddd, J=7.1, 4.9, 1.9 Hz, 1H), 3.89 (td, J=6.8, 1.9Hz, 2H), 3.82 (s, 1H), 3.69-3.40 (m, 1H), 3.23-3.06 (m, 2H), 2.89 (t,J=6.8 Hz, 2H), 2.72 (dd, J=42.6, 7.3 Hz, 2H), 2.63-2.35 (m, 2H),2.34-2.03 (m, 4H), 2.01-1.50 (m, 6H), 1.40 (dd, J=41.6, 6.8 Hz, 4H). NHproton not observed due to solvent exchange.

Example 307. Preparation of1-(5-(((2S,4R)-1-(((S)-3,3-difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 141 wherein(S)-3,3-difluorocyclopentane-1-carbaldehyde was used in place of4,4-difluorocyclohexane-1-carbaldehyde in step 7. LCMS [M+H]⁺: 460.3. ¹HNMR (400 MHz, MeOD) δ 8.43 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.36 (d,J=2.1 Hz, 1H), 6.88-6.80 (m, 1H), 3.89 (td, J=6.8, 1.8 Hz, 2H), 3.82 (s,1H), 3.23-3.05 (m, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.67 (d, J=7.0 Hz, 2H),2.62-2.37 (m, 2H), 2.31-2.05 (m, 4H), 1.98-1.52 (m, 6H), 1.47-1.22 (m,5H). NH proton not observed due to solvent exchange.

Examples 308 and 309. Preparation of1-(5-(((2S)-1-((4,4-difluorocyclohexyl)methyl)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl(2S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoro-2-methylpiperidine-1-carboxylate

To an oven-dried vial was added tert-butyl(2S)-4-(bromomethyl)-4-fluoro-2-methylpiperidine-1-carboxylate (0.270 g,0.87 mmol),1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(0.250 g, 0.544 mmol), NiCl₂(DME) (5 mg, 0.027 mmol),pyridine-2,6-bis(carboximidamide) dihydrochloride (6 mg, 0.027 mmol),NaI (0.020 g, 0.14 mmol) and Zn (0.070 g, 1.1 mmol). The vial was sealedwith a septum cap, evacuated and refilled with nitrogen 3 times. DMA (3mL) was added and the reaction was stirred at 70° C. for 17 h. Thereaction was cooled to rt, diluted with EtOAc and filtered through aplug of silica gel, eluting with EtOAc. The eluent was concentrated andthe residue was purified by silica gel column chromatography (elutedwith 50-70% EtOAc in heptane) to give tert-butyl(2S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoro-2-methylpiperidine-1-carboxylateas a mixture of diastereomers. The diastereomers were separated bychiral HPLC purification: Column: Lux Cellulose-4 250×21.2 mm I.D., 5 μmMobile phase: Phase A for n-hexane, and Phase B for 1:1 EtOH:MeOH (0.1%HCOOH); Isocratic elution: 50% (A):50% (B) Flow rate: 15 mL/min; Peak 1(145 mg), LCMS [M+H-Boc]⁺: 510.3, HPLC rt=17.04 min; Peak 2 (245 mg),LCMS [M+H-Boc]⁺: 510.3, HPLC rt=17.64 min.

Step 2:1-(5-(((2S)-1-((4,4-difluorocyclohexyl)methyl)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 308) was prepared from tert-butyl(2S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoro-2-methylpiperidine-1-carboxylate(chiral peak 1) using the method of Example 141, steps 6-8 whereintert-butyl(2S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoro-2-methylpiperidine-1-carboxylate(chiral peak 1) was used in place of tert-butyl(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylatein step 6. LCMS [M+H]⁺: 492.1. ¹H NMR (400 MHz, MeOD) δ 8.44 (dd, J=7.2,0.9 Hz, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.42 (s, 1H), 6.87 (d, J=7.2Hz, 1H), 3.90 (t, J=6.8 Hz, 2H), 3.18-3.06 (m, 2H), 2.98 (s, 2H), 2.89(t, J=6.8 Hz, 2H), 2.81 (s, 1H), 2.19-1.72 (m, 12H), 1.45-1.25 (m, 6H).

1-(5-(((2S)-1-((4,4-difluorocyclohexyl)methyl)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 309) was prepared from tert-butyl(2S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoro-2-methylpiperidine-1-carboxylate(chiral peak 2) using the method of Example 141, steps 6-8 whereintert-butyl(2S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoro-2-methylpiperidine-1-carboxylate(chiral peak 2) was used in place of tert-butyl(2S,4R)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylatein step 6. LCMS [M+H]⁺: 492.1. ¹H NMR (400 MHz, MeOD) δ 8.44 (d, J=7.2Hz, 1H), 8.33 (s, 1H), 8.03 (s, 1H), 7.43 (s, 1H), 6.87 (d, J=7.2 Hz,1H), 3.90 (t, J=6.7 Hz, 2H), 3.15-2.96 (m, 4H), 2.89 (t, J=6.8 Hz, 2H),2.69 (s, 1H), 2.13-1.72 (m, 10H), 1.29 (t, J=5.0 Hz, 8H).

Example 310. Preparation of1-(5-(((2S)-4-fluoro-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.1-(5-(((2S)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (2 mL) was added to tert-butyl(2S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoro-2-methylpiperidine-1-carboxylate(chiral peak 1 from Example 308, step 1) (350 mg, 0.574 mmol). Themixture was heated in a sealed vial for 24 h at 90° C. The mixture wasthen cooled to rt and, concentrated and azeotropically dried withtoluene to provide crude1-(5-(((2S)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewhich was used without further purification. LCMS [M+H]⁺: 360.0.

Step 2:1-(5-(((2S)-4-fluoro-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 310) was prepared from1-(5-(((2S)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneby the method of Example 279, wherein1-(5-(((2S)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride. LCMS [M+H]⁺: 416.0. ¹H NMR (400 MHz, MeOD) δ 8.41 (dd,J=7.2, 0.9 Hz, 1H), 8.00 (s, 1H), 7.40 (d, J=1.7 Hz, 1H), 6.90-6.79 (m,1H), 4.71-4.60 (m, 4H), 3.96 (q, J=7.0 Hz, 1H), 3.89 (t, J=6.8 Hz, 2H),3.06 (d, J=24.6 Hz, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.79 (ddt, J=17.7,12.0, 5.9 Hz, 2H), 2.37 (dt, J=11.9, 5.7 Hz, 1H), 1.95-1.79 (m, 3H),1.72 (td, J=13.1, 6.6 Hz, 1H), 0.98 (dd, J=6.7, 1.7 Hz, 3H). NH protonnot observed due to solvent exchange.

Example 311. Preparation of1-(5-(((2S)-4-fluoro-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 310 wherein tert-butyl(2S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoro-2-methylpiperidine-1-carboxylate(chiral peak 2 from Example 308, step 1) was used in place of tert-butyl(2S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-4-fluoro-2-methylpiperidine-1-carboxylate(chiral peak 1 from Example 308, step 1). LCMS [M+H]⁺: 416.0. ¹H NMR(400 MHz, MeOD) δ 8.41 (dd, J=7.2, 0.9 Hz, 1H), 8.00 (s, 1H), 7.42 (s,1H), 6.87 (d, J=7.2 Hz, 1H), 4.71-4.54 (m, 4H), 3.89 (t, J=6.8 Hz, 2H),2.99 (d, J=22.4 Hz, 2H), 2.89 (t, J=6.8 Hz, 2H), 2.58 (d, J=11.9 Hz,1H), 2.40 (s, 1H), 2.20-2.10 (m, 1H), 1.85-1.65 (m, 3H), 1.64-1.37 (m,2H), 0.87 (d, J=6.4 Hz, 3H).NH proton not observed due to solventexchange.

Example 312. Preparation of(cis)-1-(5-((1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.(cis)-3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

To an oven-dried vial was added(cis)-4-(bromomethyl)-1-isobutyl-2-(trifluoromethyl)piperidine (14 mg,0.049 mmol),1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(17.5 mg, 0.038 mmol), NiCl₂(DME) (1 mg, 0.001 mmol),pyridine-2,6-bis(carboximidamide) dihydrochloride (1 mg, 0.001 mmol),NaI (1 mg, 0.009 mmol) and Zn (4 mg, 0.076 mmol). The vial was sealedwith a septum cap, evacuated and refilled with nitrogen 3 times. DMA (2mL) was added and the reaction was stirred at 100° C. for 17 h. Thereaction was cooled to rt, diluted with EtOAc and filtered through aplug of silica gel, eluting with EtOAc. The eluent was concentrated togive crude(cis)-3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewhich was used without further purification. LCMS [M+H]⁺: 602.2.

Step 2:(cis)-1-(5-((1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 312) was prepared from(cis)-3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneusing the method of Example 1, step 5 wherein(cis)-3-(2,4-dimethoxybenzyl)-1-(5-((1-isobutyl-2-(trifluoromethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 452.4. ¹H NMR (400 MHz, MeOD) δ 8.40 (dd, J=7.2, 0.9 Hz,1H), 7.98 (s, 1H), 7.37 (dd, J=1.9, 1.0 Hz, 1H), 6.84 (dd, J=7.2, 1.9Hz, 1H), 3.87 (t, J=6.8 Hz, 2H), 3.27 (d, J=8.1 Hz, 1H), 3.24-3.12 (m,1H), 2.89 (t, J=6.8 Hz, 2H), 2.72 (dt, J=9.1, 6.4 Hz, 2H), 2.46 (d,J=7.4 Hz, 2H), 2.25 (dq, J=11.6, 5.6 Hz, 1H), 2.10-2.00 (m, 2H), 1.73(dddd, J=13.3, 10.5, 7.9, 3.2 Hz, 4H), 0.91 (d, J=6.5 Hz, 3H), 0.86 (d,J=6.7 Hz, 3H).

Example 313. Preparation of(R)-1-(5-((octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(R)-trifluoro((octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)borate wasused in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 383.0. ¹H NMR (400 MHz, MeOD) δ 8.49 (d, J=7.1 Hz, 1H), 8.04 (s,1H), 7.55 (s, 1H), 6.99 (dd, J=7.2, 1.8 Hz, 1H), 3.90 (t, J=6.7 Hz, 2H),3.79 (s, 2H), 3.51-3.41 (m, 2H), 3.28-3.12 (m, 3H), 3.04 (td, J=12.9,3.2 Hz, 1H), 2.89 (t, J=6.8 Hz, 2H), 2.63 (s, 1H), 2.37 (s, 1H), 1.94(dd, J=30.0, 13.6 Hz, 3H), 1.77 (q, J=13.4 Hz, 1H), 1.69-1.43 (m, 2H),1.37-1.27 (m, 1H). NH proton not observed due to solvent exchange.

Example 314. Preparation of(R)-1-(5-((4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(R)-trifluoro((4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)boratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 399.0. ¹H NMR (400 MHz, MeOD) δ 8.45 (dd, J=7.2, 0.9 Hz, 1H),8.01 (s, 1H), 7.51 (dd, J=1.9, 1.0 Hz, 1H), 7.01 (dd, J=7.2, 1.8 Hz,1H), 4.49 (ddd, J=13.3, 3.3, 1.8 Hz, 1H), 4.10 (d, J=1.7 Hz, 2H), 3.98(dd, J=12.0, 4.6 Hz, 1H), 3.90 (t, J=6.8 Hz, 2H), 3.74-3.51 (m, 4H),2.98-2.82 (m, 5H), 2.14 (td, J=11.6, 3.2 Hz, 1H), 2.06-1.94 (m, 1H). NHproton not observed due to solvent exchange.

Example 315. Preparation of(S)-1-(5-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 156, steps 1 and 4, whereinpotassium(S)-((1,1-dioxidohexahydro-5H-isothiazolo[2,3-a]pyrazin-5-yl)methyl)trifluoroboratewas used in place of potassium{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}(trifluoro)borate. LCMS[M+H]⁺: 419.0. ¹H NMR (400 MHz, MeOD) δ 8.45 (d, J=7.1 Hz, 1H), 8.01 (s,1H), 7.50 (s, 1H), 7.00 (dd, J=7.2, 1.8 Hz, 1H), 3.89 (t, J=6.8 Hz, 2H),3.65 (q, J=13.7 Hz, 2H), 3.26-3.10 (m, 3H), 3.04 (d, J=11.3 Hz, 1H),2.96 (d, J=11.5 Hz, 1H), 2.92-2.86 (m, 3H), 2.40-2.14 (m, 2H), 2.09-1.90(m, 3H). NH proton not observed due to solvent exchange.

Example 316. Preparation of1-(5-(((S)-4-(((1r,3S)-3-methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192 whereintrans-3-methoxycyclobutane-1-carbaldehyde was used in place ofcyclohexanecarbaldehyde in step 3. LCMS [M+H]⁺: 441.1. ¹H NMR (400 MHz,cd3od) δ 8.45 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.48 (s, 1H), 6.97 (dd,J=7.1, 1.9 Hz, 1H), 4.03-3.94 (m, 1H), 3.88 (t, J=6.8 Hz, 2H), 3.69-3.56(m, 2H), 3.40 (d, J=12.6 Hz, 3H), 3.22 (d, J=4.3 Hz, 3H), 3.10 (d,J=11.6 Hz, 2H), 3.02 (s, 1H), 2.87 (t, J=6.7 Hz, 2H), 2.72 (d, J=8.3 Hz,2H), 2.52 (s, 2H), 2.16 (ddt, J=36.3, 12.7, 7.4 Hz, 4H), 1.34 (d, J=6.6Hz, 3H). NH proton not observed due to solvent exchange.

Example 317. Preparation of1-(5-(((S)-4-(((1s,3R)-3-methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192 whereincis-3-methoxycyclobutane-1-carbaldehyde was used in place ofcyclohexanecarbaldehyde in step 3. LCMS [M+H]⁺: 441.3. ¹H NMR (400 MHz,cd3od) δ 8.46 (d, J=7.2 Hz, 1H), 8.02 (s, 1H), 7.50 (s, 1H), 6.99 (dd,J=7.1, 1.9 Hz, 1H), 3.89 (t, J=6.8 Hz, 2H), 3.81 (p, J=7.2 Hz, 1H),3.70-3.56 (m, 2H), 3.22 (s, 6H), 3.06-2.84 (m, 6H), 2.60-2.46 (m, 3H),2.36 (s, 1H), 2.22 (qd, J=9.1, 6.6 Hz, 1H), 1.75-1.60 (m, 2H), 1.30 (d,J=6.3 Hz, 3H). NH proton not observed due to solvent exchange.

Example 318. Preparation of1-(5-(((S)-4-(((1r,3R,4S)-3,4-difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192 wherein(1r,3R,4S)-3,4-difluorocyclopentane-1-carbaldehyde was used in place ofcyclohexanecarbaldehyde in step 3. LCMS [M+H]⁺: 461.4. ¹H NMR (400 MHz,MeOD) δ 8.46 (dd, J=7.2, 0.9 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J=1.8 Hz,1H), 6.99 (dd, J=7.2, 1.8 Hz, 1H), 5.08-4.92 (m, 1H), 4.81 (s, 1H), 3.89(t, J=6.8 Hz, 2H), 3.68-3.54 (m, 2H), 3.20-3.11 (m, 1H), 2.99 (t, J=11.1Hz, 1H), 2.93-2.75 (m, 5H), 2.53 (d, J=75.2 Hz, 3H), 2.39-2.06 (m, 4H),1.83-1.56 (m, 2H), 1.17 (d, J=6.1 Hz, 3H). NH proton not observed due tosolvent exchange.

Example 319. Preparation of1-(5-(((S)-4-(((R)-3,3-difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192 wherein(R)-3,3-difluorocyclopentane-1-carbaldehyde was used in place ofcyclohexanecarbaldehyde in step 3. LCMS [M+H]⁺: 461.2. ¹H NMR (300 MHz,CD₃OD) δ 8.45 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.50 (s, 1H), 7.05-6.94(m, 1H), 3.89 (t, J=6.7 Hz, 2H), 3.56 (d, J=3.6 Hz, 2H), 2.89 (t, J=6.7Hz, 3H), 2.74 (t, J=12.3 Hz, 3H), 2.61-1.91 (m, 11H), 1.38-1.25 (m, 2H),1.06 (d, J=6.1 Hz, 2H). NH proton not observed due to solvent exchange.

Example 320. Preparation of1-(5-(((S)-4-(((S)-3,3-difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192 wherein(S)-3,3-difluorocyclopentane-1-carbaldehyde was used in place ofcyclohexanecarbaldehyde in step 3. LCMS [M+H]⁺: 461.1. ¹H NMR (400 MHz,MeOD) δ 8.44 (d, J=7.1 Hz, 1H), 8.01 (s, 1H), 7.49 (s, 1H), 6.99 (dd,J=7.2, 1.8 Hz, 1H), 3.89 (t, J=6.8 Hz, 2H), 3.54 (d, J=6.3 Hz, 1H), 2.89(t, J=6.8 Hz, 3H), 2.79-2.63 (m, 3H), 2.50-1.90 (m, 12H), 1.32 (d,J=16.3 Hz, 1H), 1.04 (dd, J=6.1, 4.1 Hz, 3H). NH proton not observed dueto solvent exchange.

Example 321. Preparation of(S)-1-(5-((4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192 whereincyclopropanecarbaldehyde was used in place of cyclohexanecarbaldehyde instep 3. LCMS [M+H]⁺: 397.4. H NMR (500 MHz, DMSO) δ 10.47 (s, 1H), 8.64(d, J=7.2 Hz, 1H), 8.05 (s, 1H), 7.52 (s, 1H), 6.91 (dd, J=7.2, 1.8 Hz,1H), 3.79 (t, J=6.7 Hz, 2H), 3.68 (s, 4H), 3.36 (s, 1H), 3.25-3.12 (m,2H), 3.04 (d, J=14.6 Hz, 3H), 2.80 (t, J=6.7 Hz, 2H), 2.31 (d, J=11.9Hz, 1H), 1.25 (d, J=6.4 Hz, 3H), 1.05 (s, 1H), 0.65 (s, 2H), 0.39 (d,J=29.5 Hz, 2H).

Example 322. Preparation of(S)-1-(5-((3-methyl-4-((1-methylcyclobutyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 192 wherein1-methylcyclobutane-1-carbaldehyde was used in place ofcyclohexanecarbaldehyde in step 3. LCMS [M+H]⁺: 425.2. ¹H NMR (500 MHz,DMSO) δ 10.47 (s, 1H), 8.64 (d, J=7.2 Hz, 1H), 8.05 (s, 1H), 7.51 (s,1H), 6.91 (d, J=7.2 Hz, 1H), 3.79 (t, J=6.7 Hz, 6H), 2.96 (s, 6H), 2.80(t, J=6.7 Hz, 3H), 2.10 (d, J=13.4 Hz, 1H), 2.01 (d, J=9.1 Hz, 1H), 1.88(s, 1H), 1.84-1.71 (m, 2H), 1.67 (s, 1H), 1.27 (s, 6H).

Example 323. Preparation of1-(5-(((S)-3-methyl-4-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.(S)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

TFA (5 mL) was added to tert-butyl(S)-4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazine-1-carboxylate(0.24 g, 0.40 mmol). The mixture was heated in a sealed vial at 70° C.for 2 h. The mixture was then cooled to rt and, concentrated andazeotropically dried with toluene to provide crude product (0.3 g) whichwas used without further purification. LCMS [M+H]⁺: 343.9.

Step 2.1-(5-(((S)-3-methyl-4-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(1r,4r)-4-(trifluoromethyl)cyclohexane-1-carbaldehyde (0.126 g, 0.70mmol) and triethylamine (0.14 mL, 1.05 mmol) were added to a solution of(S)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(0.12 g, 0.35 mmol) in DCM (4 mL). The reaction mixture was stirred atrt for 90 min and then sodium triacetoxyborohydride (0.148 g, 0.70 mmol)was added. The reaction mixture was stirred at rt for 3 h and thenquenched with a solution of saturated aqueous NaHCO₃ and extracted threetimes with DCM. The combined organic extracts were washed with brine,dried over Na₂SO₄, filtered and concentrated. The residue was dissolvedin DMSO, filtered through a 1 micron filter and purified by reversephase HPLC using ACN/Water/0.1% formic acid. The fractions containingthe product were combined, frozen and lyophilized to afford a formatesalt of1-(5-(((S)-3-methyl-4-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 507.3. ¹H NMR (400 MHz, cd3od) δ 8.46 (d, J=7.3 Hz, 1H),8.03 (s, 1H), 7.51 (s, 1H), 6.99 (dd, J=7.1, 1.9 Hz, 1H), 3.90 (t, J=6.7Hz, 2H), 3.70-3.59 (m, 2H), 3.38 (s, 1H), 3.21 (q, J=7.4 Hz, 2H),3.04-2.95 (m, 1H), 2.89 (t, J=6.7 Hz, 3H), 2.60 (s, 2H), 2.37 (s, 1H),2.15 (dd, J=23.1, 8.1 Hz, 1H), 1.98 (d, J=12.3 Hz, 2H), 1.86 (d, J=13.1Hz, 1H), 1.72 (s, 1H), 1.43-1.23 (m, 7H), 1.10 (dt, J=21.2, 11.5 Hz,2H). NH proton not observed due to solvent exchange.

Example 324. Preparation of1-(5-(((3S)-3-methyl-4-(oxetan-2-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 323 wherein oxetane-2-carbaldehydewas used in place of(1r,4r)-4-(trifluoromethyl)cyclohexane-1-carbaldehyde in step 2. LCMS[M+H]⁺: 413.0. ¹H NMR (400 MHz, MeOD) δ 8.47 (dd, J=7.2, 0.9 Hz, 1H),8.03 (s, 1H), 7.50 (s, 1H), 6.98 (dd, J=7.2, 1.9 Hz, 1H), 5.18 (q, J=9.2Hz, 1H), 4.76-4.56 (m, 2H), 3.90 (t, J=6.8 Hz, 2H), 3.81-3.61 (m, 3H),3.57-3.37 (m, 3H), 3.24-3.10 (m, 2H), 3.08-2.78 (m, 4H), 2.66-2.29 (m,3H), 1.41-1.26 (m, 3H). NH proton not observed due to solvent exchange.

Example 325. Preparation of(S)-1-(5-((4-((2-oxaspiro[3.3]heptan-6-yl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 323 wherein2-oxaspiro[3.3]heptane-6-carbaldehyde was used in place of(1r,4r)-4-(trifluoromethyl)cyclohexane-1-carbaldehyde in step 2. LCMS[M+H]⁺: 453.2. ¹H NMR (300 MHz, cd3od) δ 8.47 (s, 1H), 8.45 (s, 1H),8.03 (s, 1H), 7.49 (s, 1H), 6.98 (dd, J=7.2, 1.9 Hz, 1H), 4.75 (s, 2H),4.57 (s, 2H), 3.89 (t, J=6.7 Hz, 2H), 3.67-3.56 (m, 2H), 3.21 (d, J=24.5Hz, 2H), 2.89 (t, J=6.5 Hz, 6H), 2.56-2.41 (m, 4H), 2.38-2.21 (m, 1H),2.04 (d, J=3.8 Hz, 2H), 1.76 (td, J=10.7, 5.4 Hz, 1H), 1.27 (d, J=6.5Hz, 3H).

Example 326. Preparation of(S)-1-(5-((4-((6,6-difluorospiro[3.3]heptan-2-yl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 323 wherein6,6-difluorospiro[3.3]heptane-2-carbaldehyde was used in place of(1r,4r)-4-(trifluoromethyl)cyclohexane-1-carbaldehyde in step 2. LCMS[M+H]⁺: 487.3. ¹H NMR (400 MHz, MeOD) δ 8.45 (dd, J=7.2, 1.0 Hz, 1H),8.02 (d, J=1.5 Hz, 1H), 7.49 (d, J=1.9 Hz, 1H), 6.98 (dt, J=7.3, 1.9 Hz,1H), 3.89 (t, J=6.8 Hz, 2H), 3.68 (dd, J=5.5, 4.0 Hz, 1H), 3.63-3.52 (m,2H), 3.22-3.11 (m, 2H), 2.93-2.75 (m, 6H), 2.75-2.55 (m, 3H), 2.55-2.37(m, 3H), 2.35-1.93 (m, 5H), 1.33-1.17 (m, 3H). NH proton not observeddue to solvent exchange.

Example 327. Preparation of(S)-1-(5-((4-(2,2-difluoroethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate by the method of Example 156, steps 3-4 using2,2-difluoroethyl trifluoromethanesulfonate in step 3. LCMS [M+H]⁺:407.0. ¹H NMR (400 MHz, MeOD) δ 8.47 (dd, J=7.2, 0.9 Hz, 1H), 8.02 (s,1H), 7.53 (dd, J=1.9, 1.0 Hz, 1H), 7.00 (dd, J=7.2, 1.8 Hz, 1H), 5.93(tt, J=56.0, 4.2 Hz, 1H), 3.90 (t, J=6.8 Hz, 2H), 3.72-3.62 (m, 2H),3.15-2.95 (m, 2H), 2.89 (t, J=6.7 Hz, 2H), 2.82 (ddd, J=9.4, 6.8, 3.7Hz, 2H), 2.76-2.58 (m, 3H), 2.44 (td, J=10.9, 2.8 Hz, 1H), 2.15 (dd,J=12.0, 8.8 Hz, 1H), 1.07 (d, J=6.2 Hz, 3H).NH proton not observed dueto solvent exchange.

Example 328. Preparation of(S)-1-(5-((4-(2,2-difluoro-3-methoxypropyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared by the method of Example 278 wherein(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride was used in place of3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride in step 1. LCMS [M+H]⁺: 451.1. ¹H NMR (300 MHz,METHANOL-d4) δ ppm 8.46 (d, J=7.3 Hz, 1H), 8.01 (s, 1H), 7.51 (s, 1H),6.99 (br d, J=6.9 Hz, 1H), 3.89 (t, J=6.8 Hz, 2H), 3.73-3.53 (m, 3H)3.39 (s, 3H), 3.18-2.99 (m, 2H), 2.88 (t, J=6.76 Hz, 2H), 2.38-2.80 (m,7H), 2.09-2.24 (m, 1H), 1.05 (d, J=6.3 Hz, 3H). NH proton not observeddue to solvent exchange.

Example 329. Preparation of(S)-1-(5-((4-cyclobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.(S)-1-(5-((4-cyclobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

To a solution of(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionehydrochloride (50 mg, 0.094 mmol) in THF (2 mL) was added cyclobutanone(20 mg, 0.28 mmol), dibutyltin dichloride (86 mg, 0.28 mmol), andtriethylamine (48 mg, 0.47 mmol). The mixture was stirred at rt for 1 hand then phenylsilane (20 mg, 0.19 mmol) was added. The reaction wasstirred in a capped vial at 80° C. for 12 h. The reaction was cooled tort, diluted with DCM and washed sequentially with water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated to givecrude(S)-1-(5-((4-cyclobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.The crude product was used in the next step without any otherpurification. LCMS [M+H]⁺: 547.6.

Step 2:(S)-1-(5-((4-cyclobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione(Example 329) was prepared using the method of Example 156, step 4,wherein(S)-1-(5-((4-cyclobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 397.2. ¹H NMR (500 MHz, DMSO) δ 10.47 (s, 1H), 8.64 (d,J=7.1 Hz, 1H), 8.05 (s, 1H), 7.50 (m, 1H), 6.90 (d, J=7.0 Hz, 1H), 3.79(t, J=6.7 Hz, 6H), 3.12 (d, J=33.9 Hz, 4H), 3.03-2.85 (m, 2H), 2.79 (t,J=6.7 Hz, 2H), 2.17 (d, J=8.0 Hz, 4H), 1.83-1.63 (m, 2H), 1.26 (dd,J=31.8, 6.6 Hz, 3H).

The compounds in the following table were prepared by the method ofExample 329, using the appropriate commercially available ketone in step1.

Example Mass No. Structure [M + H]⁺ ¹H NMR 330

427.2 (400 MHz, MeOD) δ 8.46 (dd, J = 7.2, 0.9 Hz, 1H), 8.02 (s, 1H),7.50 (dd, J = 1.9, 0.9 Hz, 1H), 6.99 (dd, J = 7.2, 1.8 Hz, 1H), 4.04 (d,J = 11.3 Hz, 2H), 3.90 (t, J = 6.8 Hz, 2H), 3.71-3.54 (m, 3H), 3.52-3.39(m, 4H), 3.25- 3.12 (m, 4H), 2.89 (t, J = 6.8 Hz, 2H), 2.81 (s, 1H),2.03 (d, J = 6.1 Hz, 1H), 1.83 (d, J = 25.3 Hz, 2H), 1.71-1.58 (m, 1H),1.36-1.27 (m, 3H). NH proton not observed due to solvent exchange. 331

399.0 (400 MHz, MeOD) δ 8.45 (dd, J = 7.2, 1.0 Hz, 1H), 8.25 (s, 1H),8.01 (s, 1H), 7.51 (dd, J = 1.9, 0.9 Hz, 1H), 6.99 (dd, J = 7.2, 1.8 Hz,1H), 4.69 (dd, J = 12.8, 6.7 Hz, 3H), 4.61 (dd, J = 7.4, 6.3 Hz, 1H),3.86 (dt, J = 21.3, 6.9 Hz, 3H), 3.68-3.56 (m, 2H), 2.89 (t, J = 6.8 Hz,2H), 2.86-2.68 (m, 3H), 2.45 (dd, J = 25.5, 14.8 Hz, 2H), 2.32-2.12 (m,2H), 0.92 (d, J = 6.5 Hz, 3H). 332

439.2 (400 MHz, MeOD) δ 8.48 (dd, J = 7.2, 0.9 Hz, 1H), 8.03 (s, 1H),7.52 (s, 1H), 7.01 (dd, J = 7.2, 1.9 Hz, 1H), 3.90 (t, J = 6.8 Hz, 3H),3.79-3.51 (m, 9H), 3.16-3.07 (m, 1H), 2.99-2.84 (m, 3H), 2.72- 2.57 (m,2H), 2.17-2.00 (m, 4H), 1.57 (d, J = 6.7 Hz, 3H). NH proton not observeddue to solvent exchange. 333

425.2 (400 MHz, MeOD) δ 8.46 (d, J = 7.1 Hz, 1H), 8.02 (s, 1H), 7.50 (d,J = 1.7 Hz, 1H), 6.99 (dd, J = 7.1, 1.8 Hz, 1H), 3.89 (t, J = 6.7 Hz,2H), 3.68-3.57 (m, 2H), 3.45 (d, J = 25.8 Hz, 1H), 3.26 (s, 2H), 2.89(t, J = 6.8 Hz, 4H), 2.41 (d, J = 60.0 Hz, 2H), 1.97 (dd, J = 42.9, 11.3Hz, 4H), 1.72 (d, J = 13.1 Hz, 1H), 1.57 (d, J = 12.0 Hz, 1H), 1.49-1.12(m, 8H). NH proton not observed due to solvent exchange. 334

461.2 (500 MHz, DMSO) δ 10.47 (s, 1H), 8.64 (d, J = 7.1 Hz, 1H), 8.05(s, 1H), 7.50 (s, 1H), 6.91 (d, J = 7.3 Hz, 1H), 3.79 (t, J = 6.8 Hz,3H), 3.62 (s, 4H), 3.03 (s, 4H), 2.80 (t, J = 6.7 Hz, 3H), 2.34 (s, 1H),2.09 (t, J = 23.8 Hz, 5H), 1.77 (s, 1H), 1.63 (s, 1H), 1.38 (d, J = 6.6Hz, 1H), 1.26 (s, 2H). 335

437.3 (400 MHz, MeOD) δ 8.47-8.44 (m, 1H), 8.02 (s, 1H), 7.49 (s, 1H),6.98 (dd, J = 7.2, 1.9 Hz, 1H), 3.89 (t, J = 6.8 Hz, 2H), 3.70- 3.54 (m,3H), 3.25 (d, J = 9.0 Hz, 1H), 2.89 (t, J = 6.8 Hz, 5H), 2.41 (ddt, J =27.4, 12.4, 6.0 Hz, 3H), 2.23 (t, J = 10.1 Hz, 1H), 2.12 (dd, J = 8.8,6.0 Hz, 3H), 2.07-1.96 (m, 3H), 1.96-1.84 (m, 2H), 1.74- 1.55 (m, 1H),1.32 (d, J = 6.6 Hz, 3H). NH proton not observed due to solventexchange.

Example 336. Preparation of(S)-1-(5-((3-methyl-4-(2-methyl-2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl(S)-6-(4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylatewas prepared using the method of Example 329, step 1, wherein tert-butyl6-oxo-2-azaspiro[3.3]heptane-2-carboxylate was used in place ofcyclobutanone. LCMS [M+H]⁺: 688.3.

Step 2.(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methyl-4-(2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate

TFA (4 mL) was added to a solution of tert-butyl(S)-6-(4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate(300 mg, 0.43 mmol) in DCM (2 mL) at rt. The reaction was stirred at rtfor 2 h and then concentrated. The residue was azeotropically dried withtoluene to give crude(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methyl-4-(2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate which was used without further purification.

Step 3.(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methyl-4-(2-methyl-2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared using the method of Example 329, step 1, whereinparaformaldehyde was used in place of cyclobutanone and triethylaminewas omitted. LCMS [M+H]⁺: 602.3.

Step 4.(S)-1-(5-((3-methyl-4-(2-methyl-2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared from(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methyl-4-(2-methyl-2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneby the method of Example 156, step 4. LCMS [M+H]⁺: 452.2. ¹H NMR (400MHz, MeOD) δ 8.44 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.48 (s, 1H), 6.98(dd, J=7.1, 1.8 Hz, 1H), 4.16 (s, 2H), 4.03 (s, 2H), 3.89 (t, J=6.8 Hz,2H), 3.16-3.09 (m, 1H), 2.93-2.79 (m, 5H), 2.70 (s, 2H), 2.60-2.17 (m,7H), 2.00 (s, 1H), 1.68 (s, 1H), 1.48-1.37 (m, 2H), 1.09 (d, J=6.4 Hz,3H). NH proton not observed due to solvent exchange.

Example 337. Preparation of(S)-1-(5-((3-methyl-4-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.(S)-1-(5-((3-methyl-4-(2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate

TFA (5 mL) was added to tert-butyl(S)-6-(4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperazin-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate(152 mg, 0.22 mmol). The reaction was stirred at 90° C. for 16 h andthen concentrated. The residue was azeotropically dried with toluene togive crude(S)-1-(5-((3-methyl-4-(2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate which was used without further purification.

Step 2:(S)-1-(5-((3-methyl-4-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared from(S)-1-(5-((3-methyl-4-(2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionetrifluoroacetate by the method of Example 283, step 1 whereinmethanesulfonyl chloride was used in place of ethylsulfonyl chloride.LCMS [M+H]⁺: 516.3. ¹H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 8.60-8.49(m, 1H), 8.13 (s, 1H), 8.00 (s, 1H), 7.43 (s, 1H), 6.86 (dd, J=7.2, 1.8Hz, 1H), 3.88 (s, 2H), 3.80-3.71 (m, 4H), 3.45 (q, J=13.7 Hz, 1H), 2.93(s, 4H), 2.77 (t, J=6.7 Hz, 2H), 2.60 (s, 1H), 2.41 (s, 1H), 2.37-2.28(m, 3H), 2.28-1.92 (m, 6H), 0.94 (d, J=6.3 Hz, 3H).

Example 338. Preparation of1-(5-((4-cyclohexylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 329 wherein3-(2,4-dimethoxybenzyl)-1-(5-(piperazin-1-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneand cyclohexanone was used in place of cyclobutanone in step 1. LCMS[M+H]⁺: 411.2. ¹H NMR (300 MHz, CD₃OD) δ 8.46 (d, J=7.1 Hz, 1H), 8.03(s, 1H), 7.50 (s, 1H), 6.99 (dd, J=7.2, 1.8 Hz, 1H), 3.89 (t, J=6.8 Hz,2H), 3.67 (s, 2H), 3.11 (s, 2H), 2.89 (t, J=6.8 Hz, 8H), 2.12 (d, J=9.2Hz, 2H), 1.94 (d, J=10.7 Hz, 2H), 1.72 (d, J=12.7 Hz, 1H), 1.53-1.15 (m,6H). NH proton not observed due to solvent exchange.

Example 339. Preparation of(S)-1-(5-((4-(ethylsulfonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared from(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dioneby the method of Example 283. LCMS [M+H]⁺: 435.1. ¹H NMR (500 MHz, DMSO)δ 10.53 (s, 1H), 8.75 (d, J=7.2 Hz, 1H), 8.14 (s, 1H), 7.71 (s, 1H),7.01 (d, J=7.2 Hz, 1H), 4.27 (d, J=76.7 Hz, 5H), 3.90-3.77 (m, 2H), 3.71(s, 1H), 3.35 (s, 2H), 3.17 (tq, J=14.3, 7.1 Hz, 3H), 2.80 (dd, J=7.4,6.1 Hz, 2H), 1.33 (d, J=7.0 Hz, 3H), 1.21 (t, J=7.3 Hz, 3H).

Example 340. Preparation of(S)-1-(5-((4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared by the method of Example 287 wherein(S)-3-(2,4-dimethoxybenzyl)-1-(5-((3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas used in place of3-(2,4-dimethoxybenzyl)-1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionein step 1. LCMS [M+H]⁺: 411.1. ¹H NMR (500 MHz, DMSO) δ 10.54 (s, 1H),8.77 (d, J=7.2 Hz, 1H), 8.15 (s, 1H), 7.73 (s, 1H), 7.10-6.93 (m, 1H),4.80 (s, 1H), 4.37 (s, 2H), 3.84 (ddd, J=10.1, 8.3, 5.0 Hz, 4H), 3.37(s, 2H), 3.01 (s, 1H), 2.80 (t, J=6.7 Hz, 2H), 1.97 (t, J=6.4 Hz, 1H),1.35 (s, 1H), 1.19 (d, J=10.9 Hz, 2H), 0.75 (s, 5H).

Example 341. Preparation of(S)-1-(5-((4-isobutyryl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 340 wherein isobutyric acid wasused in place of cyclopropanecarboxylic acid in step 1. LCMS [M+H]⁺:413.2. ¹H NMR (500 MHz, DMSO) δ 10.54 (s, 1H), 8.77 (d, J=7.2 Hz, 1H),8.15 (s, 1H), 7.73 (s, 1H), 7.02 (d, J=7.3 Hz, 1H), 4.82 (s, 2H), 4.06(s, 2H), 3.92-3.73 (m, 3H), 3.39 (d, J=41.9 Hz, 2H), 2.83 (dt, J=28.3,6.7 Hz, 3H), 2.56 (s, 1H), 1.34 (d, J=6.9 Hz, 1H), 1.18 (d, J=7.1 Hz,2H), 0.99 (dd, J=24.2, 6.9 Hz, 7H).

Example 342. Preparation of(S)-1-(5-((4-(cyclohexanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 340 wherein cyclohexanecarboxylicacid was used in place of cyclopropanecarboxylic acid in step 1. LCMS[M+H]⁺: 453.1. ¹H NMR (500 MHz, DMSO) δ 10.54 (s, 1H), 8.77 (d, J=7.2Hz, 1H), 8.15 (s, 1H), 7.72 (s, 1H), 7.02 (d, J=7.2 Hz, 1H), 4.81 (s,1H), 4.41 (d, J=69.3 Hz, 3H), 3.82 (dd, J=7.0, 5.0 Hz, 4H), 3.40 (dd,J=35.2, 21.7 Hz, 3H), 2.94 (d, J=30.7 Hz, 2H), 2.80 (dd, J=7.3, 6.1 Hz,2H), 1.71 (d, J=13.2 Hz, 2H), 1.64 (d, J=14.5 Hz, 2H), 1.31 (td, J=24.7,14.1 Hz, 5H), 1.17 (d, J=7.3 Hz, 3H).

Example 343. Preparation of(S)-1-(5-((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 340 wherein cyclopentanecarboxylicacid was used in place of cyclopropanecarboxylic acid in step 1. LCMS[M+H]⁺: 439.1. ¹H NMR (500 MHz, DMSO) δ 10.54 (s, 1H), 8.77 (s, 1H),8.15 (s, 1H), 7.72 (s, 1H), 7.02 (s, 1H), 4.81 (s, 1H), 4.37 (s, 4H),3.87-3.58 (m, 2H), 3.39 (d, J=14.3 Hz, 3H), 3.09-2.86 (m, 2H), 2.80 (t,J=6.7 Hz, 2H), 1.75 (d, J=21.2 Hz, 3H), 1.56 (d, J=33.7 Hz, 5H), 1.33(d, J=6.9 Hz, 1H), 1.18 (d, J=6.9 Hz, 2H).

Example 344. Preparation of(S)-1-(5-((4-(cyclobutanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 340 wherein cyclobutanecarboxylicacid was used in place of cyclopropanecarboxylic acid in step 1. LCMS[M+H]⁺: 425.1. ¹H NMR (500 MHz, DMSO) δ 10.53 (s, 1H), 8.76 (s, 1H),8.14 (s, 1H), 7.71 (s, 1H), 7.00 (s, 1H), 4.58 (d, J=188.4 Hz, 5H),3.90-3.72 (m, 3H), 3.50-3.17 (m, 3H), 2.97 (s, 1H), 2.80 (t, J=6.7 Hz,2H), 2.27-2.01 (m, 4H), 1.91 (p, J=8.7 Hz, 1H), 1.76 (d, J=9.3 Hz, 1H),1.29 (d, J=6.9 Hz, 1H), 1.18 (d, J=7.1 Hz, 2H).

Example 345. Preparation of1-(5-(1-(4-isobutylpiperazin-1-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

Step 1.1-(5-acetylpyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione

Tributyl(1-ethoxyvinyl)stannane (757 mg, 2.09 mmol) and Pd(PPh₃)₂Cl₂(122 mg, 0.174 mmol) were added to a solution of1-(5-bromopyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(800 mg, 1.74 mmol) in DMF (8 mL) at rt. The mixture was stirred at 90°C. for 6 h, then cooled to rt and acidified with aqueous 1 N HClsolution. The mixture was partitioned between EtOAc and water. Theorganic layer was separated, washed with brine, dried over sodiumsulfate, filtered and concentrated. The crude product was purified byflash silica gel chromatography (eluted with 45% EtOAc/hexane) to give1-(5-acetylpyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dioneas an orange solid. LCMS [M+H]⁺: 423.2.

Step 2. tert-butyl4-(1-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)ethyl)piperazine-1-carboxylate

To a solution of1-(5-acetylpyrazolo[1,5-a]pyridin-3-yl)-3-(2,4-dimethoxybenzyl)dihydropyrimidine-2,4(1H,3H)-dione(170 mg, 0.402 mmol) and tert-butyl piperazine-1-carboxylate (89 mg,0.48 mmol) in THF (5 mL) was added dibutyltin dichloride (244 mg, 0.804mmol), and triethylamine (0.17 mL, 1.2 mmol). The mixture was stirred at80° C. for 2 h and then phenylsilane (87 mg, 0.80 mmol) was added. Thereaction was stirred in a capped vial at 80° C. for 12 h. The reactionwas cooled to rt, diluted with EtOAc and washed with water. The organiclayer was dried over Na₂SO₄, filtered and concentrated to give crudetert-butyl4-(1-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)ethyl)piperazine-1-carboxylate.The crude product was used in the next step without any otherpurification. LCMS [M+H]⁺: 593.0.

Step 3.1-(5-(1-(4-isobutylpiperazin-1-yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dionewas prepared by the method of Example 192, steps 2-4 wherein tert-butyl4-(1-(3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)ethyl)piperazine-1-carboxylatewas used in place of tert-butyl4-((3-(3-(2,4-dimethoxybenzyl)-2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)piperazine-1-carboxylatein step 2 and isobutyraldehyde was used in place ofcyclohexanecarbaldehyde in step 3. LCMS [M+H]⁺: 399.2. ¹H NMR (400 MHz,MeOD) δ 8.47 (d, J=7.3 Hz, 1H), 8.03 (s, 1H), 7.51-7.47 (m, 1H), 7.02(dd, J=7.3, 1.9 Hz, 1H), 3.90 (t, J=6.8 Hz, 2H), 3.67 (q, J=6.6 Hz, 1H),3.25-2.55 (m, 12H), 2.08 (dq, J=15.4, 7.6 Hz, 1H), 1.45 (d, J=6.7 Hz,3H), 1.02 (d, J=6.6 Hz, 6H). NH proton not observed due to solventexchange.

Example 346. Preparation of1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Step 1. tert-butyl(2S,4R)-2-methyl-4-(pyrazolo[1,5-a]pyridin-5-ylmethyl)piperidine-1-carboxylate

To an oven-dried vial was added 5-bromopyrazolo[1,5-a]pyridine (100 mg,507 μmol), nickel chloride, dimethoxyethane adduct (5.6 mg, 25 μmol),pyridine-2,6-bis(carboximidamide)-hydrochloride (6.0 mg, 25 μmol),activated zinc (83 mg, 1.3 mmol), tert-butyl(2S,4R)-4-(bromomethyl)-2-methylpiperidine-1-carboxylate (178 mg, 609μmol) and sodium iodide (19 mg, 127 μmol). The reaction was sealed witha septa-top cap and purged with N₂ via needle. DMA (2 mL) was added, andthe reaction was heated overnight at 70° C. The reaction was cooled tort, diluted with EtOAc and filtered through a plug of silica gel,eluting with EtOAc. The eluent was concentrated and the residue waspurified by silica gel column chromatography (eluted with 0-100% EtOAcin heptane) to give tert-butyl(2S,4R)-2-methyl-4-(pyrazolo[1,5-a]pyridin-5-ylmethyl)piperidine-1-carboxylateas a sticky solid. LCMS [M+H]⁺: 330.3.

Step 2: tert-butyl(2S,4R)-4-((3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate

To a solution of tert-butyl (2S,4R)-2-methyl-4-(pyrazolo[1,5-a]pyridin-5-ylmethyl) piperidine-1-carboxylate (220 mg, 668 μmol) in MeCN(5 mL) at 0° C. was added NIS (180 mg, 801 μmol). The reaction was thenstirred at rt for 1 h. The reaction was quenched by addition of aqueousNa₂S₂O₃ solution and extracted with EtOAc. The organic layer was washedsequentially with water and brine, dried over Na₂SO₄, filtered andconcentrated. Silica gel column chromatography (eluting with 0-100%EtOAc in heptane) provided tert-butyl (2S,4R)-4-((3-iodopyrazolo[1,5-a]pyridin-5-yl) methyl)-2-methylpiperidine-1-carboxylate as a transparentsticky solid. LCMS [M+H]⁺: 456.1.

Step 3: tert-butyl(2S,4R)-4-((3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate

To an oven-dried vial was added a solution of tert-butyl(2S,4R)-4-((3-iodopyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate(80 mg, 176 μmol) in DMSO (0.5 mL), pyrimidine-2,4(1H,3H)-dione (uracil)(26 mg, 228 μmol), potassium phosphate (78 mg, 369 μmol),N-(2-cyanophenyl) picolinamide (16 mg, 70 μmol) and copper(I) iodide(6.7 mg, 35 μmol).

The vial was sealed with a septa-top cap and purged with N₂ via needle.The reaction was heated at 110° C. for 72 h. The reaction was quenchedwith aqueous 1M KHSO₄ and extracted with EtOAc. The organic layer wasdried over Na₂SO₄, filtered and concentrated. Silica gel columnchromatography (EtOAc/heptane) provided tert-butyl(2S,4R)-4-((3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate.LCMS [M+H]⁺: 440.2.

Step 4:1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dionetrifluoroacetate

To a solution of tert-butyl(2S,4R)-4-((3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2-methylpiperidine-1-carboxylate(35 mg, 80 μmol) in DCM (2 mL) was added TFA (2 mL). The reaction wasstirred at rt for 45 min. The reaction was concentrated and the crudematerial was azeotropically dried with toluene to give crude1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dionetrifluoroacetate which used without further purification. LCMS [M+H]⁺:340.2.

Step 5:1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione(Example 346)

To a solution of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dionetrifluoroacetate (36 mg, 79 μmol) in DCM (2 mL) and MeOH (500 μL) wasadded isobutyraldehyde (14 μL, 159 μmol) and triethylamine (10 μL, 71μmol). The reaction was stirred at rt for 10 min and then sodiumtriacetoxyborohydride (84 mg, 397 μmol) was added. The reaction wasstirred at rt overnight. The reaction was quenched with one drop of TFAand then concentrated. The crude material was dissolved in DMSO,filtered through a 1 micron filter and purified by reverse phase HPLCusing ACN/Water/0.1% TFA to afford1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 396.2. ¹H NMR (500 MHz, DMSO) δ 11.51 (s, 1H), 8.67 (t,J=26.8 Hz, 1H), 8.14 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 7.36 (d, J=14.1Hz, 1H), 6.87 (s, 1H), 5.71 (s, 1H), 3.59 (d, J=89.5 Hz, 1H), 3.23-2.69(m, 2H), 2.59 (d, J=47.7 Hz, 1H), 2.36 (s, 1H), 2.23-1.81 (m, 2H),1.78-1.14 (m, 7H), 0.89 (d, J=69.0 Hz, 8H).

Example 347. Preparation of1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 346 wherein5-methylpyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 3. LCMS [M+H]⁺: 410.2. ¹H NMR (500MHz, DMSO) δ 11.53 (d, J=6.5 Hz, 1H), 8.73-8.54 (m, 1H), 8.15 (d, J=1.4Hz, 1H), 7.62 (dd, J=8.8, 1.4 Hz, 1H), 7.42-7.23 (m, 1H), 6.89 (dd,J=7.2, 1.9 Hz, 1H), 3.69 (s, 1H), 3.24-2.90 (m, 3H), 2.89-2.69 (m, 2H),2.60 (h, J=6.6 Hz, 1H), 2.23-1.88 (m, 2H), 1.83 (d, J=1.2 Hz, 3H),1.77-1.61 (m, 3H), 1.61-1.43 (m, 1H), 1.34 (d, J=6.6 Hz, 1H), 1.22 (d,J=6.8 Hz, 2H), 1.03-0.88 (m, 6H).

Example 348. Preparation of1-(5-(((2S,4R)-1-(cyclopropylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 346 wherein5-methylpyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 3 and cyclopropanecarbaldehyde wasused in place of isobutyraldehyde in step 5. LCMS [M+H]⁺: 408.2. ¹H NMR(500 MHz, DMSO) δ 11.53 (d, J=5.4 Hz, 1H), 8.69 (dt, J=7.2, 1.4 Hz, 1H),8.16 (d, J=1.4 Hz, 1H), 7.63 (dd, J=9.4, 1.4 Hz, 1H), 7.37 (dd, J=14.6,1.8 Hz, 1H), 6.90 (ddd, J=7.2, 3.6, 1.8 Hz, 1H), 3.65 (s, 1H), 3.44 (s,1H), 3.37-2.93 (m, 3H), 2.75 (dd, J=14.9, 7.2 Hz, 1H), 2.69-2.56 (m,1H), 2.26-2.03 (m, 1H), 1.83 (d, J=1.2 Hz, 3H), 1.80-1.53 (m, 3H),1.51-1.37 (m, 1H), 1.32 (d, J=6.6 Hz, 1H), 1.23 (d, J=6.9 Hz, 2H), 1.05(dt, J=27.2, 7.1 Hz, 1H), 0.73-0.53 (m, 2H), 0.49-0.22 (m, 2H).

Example 349. Preparation of5-fluoro-1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 346 wherein5-fluoropyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 3. LCMS [M+H]⁺: 414.4. ¹H NMR (500MHz, DMSO) δ 12.04 (dd, J=8.4, 5.2 Hz, 1H), 8.69 (dd, J=7.3, 2.7 Hz,1H), 8.29-8.06 (m, 2H), 7.51-7.37 (m, 1H), 6.97-6.82 (m, 1H), 3.38 (d,J=11.0 Hz, 1H), 2.97 (dt, J=12.7, 6.1 Hz, 3H), 2.90-2.70 (m, 2H), 2.61(tt, J=13.0, 7.0 Hz, 1H), 2.29-1.91 (m, 2H), 1.68 (d, J=4.5 Hz, 3H),1.62-1.44 (m, 1H), 1.35 (d, J=6.6 Hz, 1H), 1.23 (d, J=6.8 Hz, 2H),1.08-0.83 (m, 6H).

Example 350. Preparation of1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 346 wherein5-fluoropyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 3 and4,4-difluorocyclohexane-1-carbaldehyde was used in place ofisobutyraldehyde in step 5. LCMS [M+H]⁺: 490.4. ¹H NMR (500 MHz, DMSO) δ8.92 (s, 1H), 8.68 (dd, J=7.2, 3.2 Hz, 1H), 8.22 (dd, J=10.6, 6.5 Hz,1H), 8.14 (d, J=2.0 Hz, 1H), 7.43 (d, J=17.7 Hz, 1H), 6.89 (d, J=7.2 Hz,1H), 3.40-2.98 (m, 4H), 2.90 (t, J=6.2 Hz, 1H), 2.76-2.53 (m, 2H),2.23-1.98 (m, 3H), 1.96-1.42 (m, 9H), 1.28 (dd, J=54.9, 6.8 Hz, 5H).

Example 351. Preparation of1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 346 wherein5-methylpyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 3 and4,4-difluorocyclohexane-1-carbaldehyde was used in place ofisobutyraldehyde in step 5. LCMS [M+H]⁺: 486.4. ¹H NMR (500 MHz, DMSO) δ8.89 (s, 1H), 8.67 (dd, J=7.2, 3.2 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.61(dd, J=9.8, 1.5 Hz, 1H), 7.34 (d, J=16.0 Hz, 1H), 6.87 (dd, J=7.2, 1.9Hz, 1H), 3.73 (s, 1H), 3.53 (s, 1H), 3.28-2.97 (m, 2H), 2.89 (t, J=6.1Hz, 1H), 2.75-2.53 (m, 2H), 2.10 (d, J=80.9 Hz, 3H), 1.93-1.42 (m, 12H),1.27 (dd, J=53.7, 6.8 Hz, 5H).

Example 352. Preparation of5-chloro-1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 346 wherein5-chloropyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 3 and4,4-difluorocyclohexane-1-carbaldehyde was used in place ofisobutyraldehyde in step 5. LCMS [M+H]⁺: 506.4. ¹H NMR (500 MHz, DMSO) δ8.86 (s, 1H), 8.68 (dd, J=7.2, 3.0 Hz, 1H), 8.24 (d, J=9.9 Hz, 1H), 8.16(d, J=2.0 Hz, 1H), 7.43 (d, J=19.0 Hz, 1H), 6.91-6.85 (m, 1H), 3.41-2.99(m, 4H), 2.90 (t, J=6.2 Hz, 1H), 2.75-2.54 (m, 2H), 2.24-1.95 (m, 3H),1.95-1.41 (m, 9H), 1.27 (dd, J=54.4, 6.8 Hz, 5H).

Example 353. Preparation of1-(5-(((2S,4R)-1-((4,4-difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methoxypyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 346 wherein5-methoxypyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 3 and4,4-difluorocyclohexane-1-carbaldehyde was used in place ofisobutyraldehyde in step 5. LCMS [M+H]⁺: 502.2. ¹H NMR (500 MHz, DMSO) δ11.67 (s, 1H), 8.63 (d, J=7.1 Hz, 1H), 8.15 (s, 1H), 7.36 (d, J=4.2 Hz,2H), 6.97-6.76 (m, 1H), 3.63 (s, 3H), 2.91 (s, 1H), 2.44-2.32 (m, 3H),2.19 (s, 2H), 2.05-1.68 (m, 8H), 1.47 (d, J=52.8 Hz, 4H), 1.22 (d,J=25.8 Hz, 1H), 1.08 (d, J=12.7 Hz, 2H), 0.88 (s, 3H).

Example 354. Preparation of5-cyclopropyl-1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 346 wherein5-cyclopropylpyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 3. LCMS [M+H]⁺: 436.2. ¹H NMR (500MHz, DMSO) δ 11.52 (d, J=7.0 Hz, 1H), 8.68 (dd, J=7.2, 2.7 Hz, 1H), 8.15(d, J=1.5 Hz, 1H), 7.44-7.24 (m, 2H), 6.88 (d, J=7.1 Hz, 1H), 3.70 (s,2H), 3.24-2.90 (m, 2H), 2.90-2.70 (m, 2H), 2.69-2.56 (m, 3H), 2.30-1.92(m, 1H), 1.85-1.42 (m, 4H), 1.34 (d, J=6.5 Hz, 1H), 1.22 (d, J=6.8 Hz,2H), 1.09-0.87 (m, 6H), 0.71 (dt, J=8.8, 2.9 Hz, 2H), 0.68-0.57 (m, 2H).

Example 355. Preparation of1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

HATU (38 mg, 0.099 mmol) and cyclopropanecarboxylic acid (8.5 mg, 0.099mmol) were added to a solution of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dionetrifluoroacetate (30 mg, 0.066 mmol) in DMF (1.5 mL) at rt. The mixturewas stirred at rt for 5 min and then DIPEA (0.035 mL, 0.19 mmol) wasadded. The mixture was stirred at rt overnight and then filtered througha 1 micron filter and purified by reverse phase HPLC usingACN/Water/0.1% TFA to afford1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione.LCMS [M+H]⁺: 408.2. ¹H NMR (500 MHz, DMSO) δ 11.52 (d, J=2.3 Hz, 1H),8.66 (dd, J=7.2, 0.9 Hz, 1H), 8.15 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.37(d, J=1.6 Hz, 1H), 6.90 (dd, J=7.2, 1.9 Hz, 1H), 5.72 (dd, J=7.8, 2.3Hz, 1H), 4.68 (d, J=66.7 Hz, 1H), 4.19 (dd, J=89.6, 13.7 Hz, 1H), 3.12(t, J=13.1 Hz, 1H), 2.86-2.56 (m, 2H), 2.19-1.82 (m, 2H), 1.74-1.45 (m,2H), 1.43-1.22 (m, 1H), 1.21-0.90 (m, 4H), 0.80-0.46 (m, 4H).

Example 356. Preparation of1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Triethylamine (0.046 mL, 0.33 mmol) and ethylsulfonyl chloride (0.019mL, 0.19 mmol) were added to a solution of1-(5-(((2S,4R)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dionetrifluoroacetate (30 mg, 0.066 mmol) in DCM (2 mL) at 0° C. The mixturewas stirred at rt overnight and then filtered through a 1 micron filterand purified by reverse phase HPLC using ACN/Water/0.1% TFA to afford1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione(8 mg, 14 μmol, 21% yield). LCMS [M+H]⁺: 432.5. ¹H NMR (500 MHz, DMSO) δ11.52 (d, J=2.3 Hz, 1H), 8.66 (d, J=7.1 Hz, 1H), 8.15 (s, 1H), 7.73 (dd,J=7.8, 1.2 Hz, 1H), 7.37 (s, 1H), 6.89 (dd, J=7.2, 1.8 Hz, 1H), 5.72(dd, J=7.8, 2.3 Hz, 1H), 4.05 (t, J=6.3 Hz, 1H), 3.49 (s, 1H), 3.14-2.86(m, 3H), 2.59-2.54 (m, 2H), 2.03 (s, 1H), 1.55 (dd, J=32.4, 13.3 Hz,2H), 1.37 (td, J=12.8, 5.3 Hz, 1H), 1.18 (t, J=7.3 Hz, 6H), 1.14-1.07(m, 1H).

Example 357. Preparation of(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Step 1: tert-butyl(S)-2-methyl-4-(pyrazolo[1,5-a]pyridin-5-ylmethyl)piperazine-1-carboxylate

To a suspension of 5-bromopyrazolo[1,5-a]pyridine (500 mg, 2.54 mmol) intoluene (10 mL) and water (1 mL) at room temperature was added Cs₂CO₃(2.48 g, 7.61 mmol), tert-butyl(S)-2-methyl-4-((trifluoro-l4-boraneyl)methyl)piperazine-1-carboxylate,potassium salt (2.44 g, 7.61 mmol) and RuPhos (237 mg, 0.508 mmol),followed by Pd(OAc)₂ (57 mg, 0.25 μmol). The mixture was stirred at 100°C. overnight, then cooled to rt and partitioned between EtOAc and water.The organic layer was separated, washed with brine, dried over sodiumsulfate, filtered and concentrated. Silica gel column chromatography(EtOAc/EtOH/heptane) provided tert-butyl(S)-2-methyl-4-(pyrazolo[1,5-a]pyridin-5-ylmethyl)piperazine-1-carboxylate(735 mg, 1.9 mmol, 75% yield). LCMS [M+H]⁺: 331.4.

Step 2.(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dionewas prepared by the method of Example 346, steps 2-5 wherein tert-butyl(S)-2-methyl-4-(pyrazolo[1,5-a]pyridin-5-ylmethyl)piperazine-1-carboxylatewas used in place of tert-butyl(2S,4R)-2-methyl-4-(pyrazolo[1,5-a]pyridin-5-ylmethyl)piperidine-1-carboxylatein step 2. LCMS [M+H]⁺: 397.2. ¹H NMR (500 MHz, DMSO) δ 11.54 (s, 1H),8.80-8.57 (m, 1H), 8.19 (s, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.48 (d, J=22.7Hz, 1H), 6.98 (d, J=7.1 Hz, 1H), 5.73 (d, J=8.2 Hz, 1H), 3.64 (d, J=14.1Hz, 1H), 3.52 (t, J=15.9 Hz, 1H), 3.21-2.99 (m, 1H), 2.92 (d, J=13.0 Hz,2H), 2.80-2.64 (m, 1H), 2.49-2.28 (m, 2H), 2.29-1.58 (m, 2H), 1.29 (d,J=6.4 Hz, 2H), 0.98 (dd, J=15.1, 6.6 Hz, 5H), 0.85 (s, 2H). Two missingprotons attributed to overlap with solvent.

Example 358. Preparation of(S)-5-fluoro-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 357 wherein5-fluoropyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 2. LCMS [M+H]⁺: 415.2. ¹H NMR (500MHz, DMSO) δ 12.05 (d, J=5.3 Hz, 1H), 8.74 (d, J=7.2 Hz, 1H), 8.23 (d,J=6.4 Hz, 1H), 8.19 (s, 1H), 7.59 (s, 1H), 6.99 (dd, J=7.1, 1.8 Hz, 1H),3.51 (s, 4H), 3.21-2.72 (m, 7H), 2.21-1.75 (m, 1H), 1.27 (s, 3H), 0.97(t, J=6.7 Hz, 6H).

Example 359. Preparation of(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 357 wherein5-methylpyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 2. LCMS [M+H]⁺: 411.2. ¹H NMR (500MHz, DMSO) δ 11.52 (s, 1H), 8.71 (dd, J=7.1, 0.9 Hz, 1H), 8.17 (s, 1H),7.61 (q, J=1.2 Hz, 1H), 7.50 (s, 1H), 6.97 (dd, J=7.2, 1.8 Hz, 1H), 3.72(s, 5H), 3.05 (s, 4H), 2.75 (d, J=59.3 Hz, 2H), 2.01 (s, 1H), 1.81 (d,J=1.3 Hz, 3H), 1.26 (d, J=6.4 Hz, 3H), 0.94 (t, J=6.7 Hz, 6H).

Example 360. Preparation of(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methoxypyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 357 wherein5-methoxypyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 2. LCMS [M+H]⁺: 427.2. ¹H NMR (500MHz, DMSO) δ 11.71 (s, 1H), 8.73 (d, J=7.2 Hz, 1H), 8.21 (s, 1H), 7.53(s, 1H), 7.37 (s, 1H), 6.98 (d, J=7.2 Hz, 1H), 3.64 (s, 8H), 2.93 (d,J=47.3 Hz, 5H), 2.38 (s, 1H), 2.03 (s, 1H), 1.49-1.14 (m, 3H), 0.96 (t,J=6.3 Hz, 6H).

Example 361. Preparation of(S)-5-cyclopropyl-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 357 wherein5-cyclopropylpyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione in step 2. LCMS [M+H]⁺: 437.2. ¹H NMR (500MHz, DMSO) δ 11.53 (s, 1H), 8.72 (d, J=7.1 Hz, 1H), 8.19 (s, 1H), 7.49(d, J=14.4 Hz, 1H), 7.35 (d, J=0.9 Hz, 1H), 6.97 (dd, J=7.2, 1.8 Hz,1H), 3.52 (s, 5H), 2.94 (d, J=49.6 Hz, 5H), 2.38 (s, 1H), 2.03 (s, 1H),1.65 (ddd, J=11.0, 8.6, 5.3 Hz, 1H), 1.39-1.16 (m, 3H), 0.96 (t, J=6.6Hz, 6H), 0.81-0.67 (m, 2H), 0.65-0.47 (m, 2H).

Example 362. Preparation of(S)-1-(5-((4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 357 wherein5-methylpyrimidine-2,4(1H,3H)-dione was used in place ofpyrimidine-2,4(1H,3H)-dione and cyclopropanecarbaldehyde was used inplace of isobutyraldehyde in step 2. LCMS [M+H]⁺: 409.2. ¹H NMR (500MHz, DMSO) δ 11.54 (s, 1H), 8.73 (d, J=7.3 Hz, 1H), 8.19 (s, 1H), 7.64(d, J=1.4 Hz, 1H), 7.50 (s, 1H), 6.98 (dd, J=7.2, 1.8 Hz, 1H), 3.67 (d,J=13.9 Hz, 2H), 3.35 (s, 2H), 3.17 (d, J=11.8 Hz, 2H), 3.01 (t, J=13.6Hz, 3H), 2.25 (t, J=11.8 Hz, 1H), 1.83 (d, J=1.3 Hz, 3H), 1.32 (d, J=6.6Hz, 1H), 1.24 (d, J=6.4 Hz, 3H), 1.05 (s, 1H), 0.65 (d, J=13.3 Hz, 2H),0.50-0.15 (m, 2H).

Example 363. Preparation of(S)-1-(5-((4-((4,4-difluorocyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

Prepared using the method of Example 357 wherein4,4-difluorocyclohexane-1-carbaldehyde was used in place ofisobutyraldehyde in step 2. LCMS [M+H]⁺: 473.2. ¹H NMR (500 MHz, DMSO) δ11.56 (s, 1H), 8.74 (d, J=7.2 Hz, 1H), 8.21 (s, 1H), 7.74 (d, J=7.7 Hz,1H), 7.52 (s, 1H), 7.14-6.62 (m, 1H), 5.82-5.52 (m, 1H), 4.19 (s, 2H),3.68 (s, 3H), 3.29 (s, 2H), 2.99 (s, 3H), 2.36 (d, J=19.6 Hz, 1H), 2.04(s, 2H), 1.96-1.59 (m, 5H), 1.26 (s, 5H).

BIOLOGICAL DATA Abbreviations

BSA bovine serum albuminCas9 CRISPR associated protein 9CRISPR Clustered regularly interspaced short palindromic repeatscrRNA CRISPR RNADMEM Dulbecco's modified eagle mediaDMSO Dimethyl sulfoxide

DTT Dithiothreitol

EDTA ethylenediaminetetraacetic acideGFP enhanced green fluorescent proteinFACS fluorescence-activated cell sortingFBS fetal bovine serumFITC fluoresceinFIt3L Fms-related tyrosine kinase 3 ligand, FIt3LHbF Fetal hemoglobinHEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)IMDM Iscove's modified Dulbecco's mediumKCl potassium chloridemPB mobilized peripheral bloodPBS phosphate buffered salinerhEPO recombinant human erythropoietinrhIL-3 recombinant human interleukin-3rhIL-6 recombinant human interleukin-6rhSCF recombinant human stem cell factorrhTPO recombinant human thrombopoietinRNP ribonucleoproteinshRNA short hairpin RNAtracrRNA trans-activating crRNA

WIZ Widely-Interspaced Zinc Finger Containing Protein Materials andMethods Example 364: Quantification of WIZ Protein Levels in HiBit TagFusion Protein Assay

The HiBit system from Promega was used to develop high-throughput andquantitative assays to measure changes in WIZ protein levels in responseto compounds. The HiBit tag was derived from a split Nanoluciferase andhas the following protein sequence: VSGWRLFKKIS (SEQ ID NO: 1). Thecomplementary fragment of Nanoluciferase (known as LgBit, from Promega),was added to the HiBit tag to form an active Nanoluciferase enzyme whoseactivity can be precisely measured. In this way, the levels of a fusionprotein with the HiBit tag can be quantified in cell lysates.

Lentiviral vectors, based on the Invitrogen™ pLenti6.2/V5 DEST backbonewere constructed that places the HiBit tag upstream of WIZ and expressedthe fusion protein from an HSVTK promotor.

To ensure moderate and consistent expression of the HiBit-WIZ fusionprotein across all cells in the population, stable cell lines wereconstructed from cells harboring a single copy of the construct.Lentivirus packaged with the constructs were made using the ViraPower™kit from Invitrogen™. 293T cells from ATCC (Catalog number: CRL-3216),were infected with the virus at low multiplicity of infection andselected by 5 μg/mL blasticidin in culture media for 2 weeks.

The levels of HiBit-WIZ tagged fusion proteins in compound-treated celllines were measured as follows:

On day 1, cells were diluted to 1.0×10⁶ cells/ml in normal growthmedium. 20 μL of cell suspension were plated in each well of a solidwhite 384-well plate. Plates were incubated overnight in a 37° C. and 5%CO₂ humidified tissue culture incubator.

On day 2, serial dilutions of compounds were made in 384-well plates.Compound plates were set up with DMSO in columns 1, 2, 23, 24, and10-point compound dilution series in column 3-12 and column 13-22. 10 mMstock solution of compound were placed into column 3 or 13 and a 1:5serial dilution was carried out until there was a 10-point dilutionseries per compound. 50 nL of diluted compounds were transferred intothe plated cells by Echo® (Labcyte) acoustic transfer. The highestconcentration of compound was 25 μM. Plates were incubated overnight(about 18 hours) in a 37° C. and 5% CO₂ humidified tissue cultureincubator.

On day 3, plates were removed from the incubator and allowed toequilibrate at room temperature for 60 minutes. HiBit substrate(Nano-Glo® HiBit Lytic Detection System, Promega Catalogue number:N3050) was added as described by the manufacturers protocols. Plateswere incubated at room temperature for 30 minutes and luminescence wasread using an EnVision® reader (PerkinElmer®). Data was analyzed andvisualized using the Spotfire® software package.

WIZ Degradation Activity of Compounds (Table 1)

Table 1 shows WIZ degradation activity of compounds of the disclosure inthe WIZ HiBit assay in 293T cells. WIZ Amax reflects theDMSO-normalized, curve-fitted percentage of WIZ-HiBit remaining at 25uM. It was calculated by normalizing DM75 controls to 100%, parametriccurve fitting of the dose response data (10-point, 5-fold), followed bycalculation of response at 25 uM using the fitted equation (nd=notdetermined).

TABLE 1 WIZ % degradation Cmpd AC₅₀ WIZ of WIZ No. (μM) Amax (100 −Amax)  1 0.020 9 91  2 0.023 9 91  3 0.020 10 90  4 0.005 10 90  5 0.20411 89  6 0.013 11 89  7 0.023 14 86  8 0.008 14 86  9 0.031 16 84  100.004 16 84  11 0.055 16 84  12 0.051 16 84  13 0.019 16 84  14 0.028 1684  15 0.523 29 71  16 0.018 16 84  17 0.048 18 82  18 0.034 18 82  190.020 19 81  20 0.022 21 79  21 0.025 22 78  22 0.071 23 77  23 0.144 2377  24 1.075 23 77  25 0.040 24 76  26 0.297 24 76  27 0.046 24 76  280.105 25 75  29 0.232 26 74  30 0.201 20 80  31 0.027 26 74  32 0.023 1882  33 0.031 27 73  34 0.945 27 73  35 3.138 27 73  36 0.068 28 72  370.446 28 72  38 0.112 29 71  39 0.083 29 71  39a 0.087 32 68  40 0.05230 70  41 0.027 30 70  42 0.026 30 70  43 0.034 30 70  44 0.043 30 70 45 0.023 30 70  46 0.058 31 69  47 0.157 31 69  48 0.061 32 68  492.787 34 66  50 0.113 34 66  51 0.039 34 66  52 0.987 41 59  53 0.037 3565  54 0.044 36 64  55 0.103 36 64  56 0.204 37 63  57 0.107 37 63  580.033 37 63  59 0.098 42 58  60 0.034 39 61  61 1.739 38 62  62 0.049 2773  63 >25 64 36  64 0.043 6 94  65 0.032 6 94  66 0.195 28 72  67 0.56139 61  68 0.384 43 57  69 0.350 65 35  70 0.021 17 83  71 0.007 15 85 72 0.006 13 87  73 0.003 11 89  74 0.003 10 90  75 0.098 19 81  760.036 19 81  77 0.077 32 68  78 0.010 17 83  79 0.065 35 65  80 0.049 1288  81 0.015 8 92  82 0.033 10 90  83 0.076 11 89  84 0.055 13 87  850.038 17 83  86 0.027 20 80  87 0.025 21 79  88 0.181 22 78  89 0.285 2377  90 2.002 23 77  91 0.150 26 74  92 0.131 31 69  93 6.518 38 62  943.993 38 62  95 >25 57 43  96 >25 58 42  97 24.763 56 44  98 0.587 41 59 99 1.833 48 52 100 0.755 58 42 101 >25 67 33 102 0.165 60 40 103 0.08272 28 104 7.365 38 62 105 2.156 36 64 106 0.283 32 68 107 0.031 22 78108 1.341 66 34 109 0.039 18 82 110 0.044 21 79 111 0.304 44 56 1120.016 34 66 113 0.004 12 88 114 0.090 32 68 115 0.267 46 54 116 1.700 6139 117 0.001 10 90 118 0.166 36 64 119 0.109 18 82 120 1.434 34 66121 >25 50 50 122 2.577 45 55 123 0.095 32 68 124 0.502 42 58 125 0.59645 55 126 0.29 65 35 127 0.013 31 69 128 0.83 71 29 129 0.80 65 35 1301.32 64 36 131 0.37 62 38 132 0.72 59 41 133 4.8 79 21 134 4.3 73 27 1352.1 74 26 136 0.033 14 86 137 0.121 23 77 138 0.10 20 80 139 0.003 17 83140 0.007 10 90 141 0.002 9 91 142 0.011 11 89 143 0.004 12 88 144 0.00813 87 145 0.025 16 84 146 0.051 18 82 147 0.005 10 90 148 0.063 14 86149 0.0004 10 90 150 0.0003 10 90 151 0.27 14 86 152 0.91 19 81 1530.014 14 86 154 0.041 22 78 155 0.009 15 85 156 0.023 14 86 157 0.022 1783 158 0.025 18 82 159 0.023 19 81 160 0.045 18 82 161 0.115 20 80 1620.079 21 79 163 0.561 24 76 164 0.323 31 69 165 0.198 31 69 166 0.632 3466 167 0.286 43 57 168 0.127 44 56 169 0.326 45 55 170 0.228 47 53 1710.981 48 52 172 0.527 58 42 173 0.771 58 42 174 0.095 19 81 175 1.240 6040 176 1.396 62 38 177 0.106 23 77 178 0.048 24 76 179 0.049 18 82 1800.078 19 81 181 0.030 25 75 182 0.199 33 67 183 0.468 35 65 184 1.627 7129 185 0.582 53 47 186 0.076 21 79 187 0.020 20 80 188 0.071 23 77 1890.191 29 71 190 0.086 46 54 191 0.683 50 50 192 0.019 14 86 193 0.010 1486 194 0.003 11 89 195 2.047 52 48 196 3.821 59 41 197 1.144 60 40 1980.009 13 87 199 0.009 14 86 200 0.008 10 90 201 0.020 12 88 202 0.005 1585 203 0.025 16 84 204 0.051 16 84 205 0.024 18 82 206 0.193 22 78 2070.014 14 86 208 0.580 40 60 209 0.38 26 74 210 0.016 14 86 211 0.033 1486 212 0.029 16 84 213 0.048 19 81 214 0.151 35 65 215 2.617 81 19 2160.089 35 65 217 0.092 25 75 218 0.068 29 71 219 0.212 25 75 220 0.133 3466 221 0.318 46 54 222 0.457 36 64 223 0.877 49 51 224 0.854 55 45 2251.050 68 32 226 1.233 55 45 227 0.956 40 60 228 0.704 45 55 229 >25 1000 230 >25 100 0 231 0.15 47 53 232 0.206 52 48 233 0.589 60 40 234 0.94258 42 235 3.277 65 35 236 3.198 95 5 237 >25 94 6 238 0.754 81 19239 >25 100 0 240 0.025 20 80 241 0.351 56 44 242 1.604 93 7 243 3.06587 13 244 1.179 47 53 245 0.351 48 52 246 >25 100 0 247 1.371 85 15248 >25 100 0 249 0.30 59 41 250 1.35 59 41 251 0.165 82 18 252 0.277 5842 253 0.531 77 23 254 >25 100 0 255 >25 100 0 256 0.186 22 78 257 0.10126 74 258 0.148 31 69 259 0.258 39 61 260 0.796 32 68 261 0.417 37 63262 0.583 32 68 263 0.88 45 55 264 0.26 36 64 266 0.044 19 81 267 0.1014 86 268 0.024 11 89 269 1.02 51 49 270 0.099 43 57 271 0.702 37 63 2720.025 31 69 273 0.040 22 78 274 0.032 23 77 275 0.020 21 79 276 0.009 1584 277 0.203 24 76 278 0.066 28 72 279 0.026 9 91 280 0.008 12 88 2810.004 17 83 282 0.001 19 81 283 0.029 19 80 284 0.018 20 80 285 0.003 1882 286 0.031 20 79 287 0.015 19 81 288 0.008 20 80 289 0.033 21 79 2901.70 46 54 291 0.015 17 83 292 0.011 17 83 293 0.065 24 76 294 0.018 1981 295 0.024 20 80 296 0.010 23 77 297 0.029 32 68 298 0.242 49 51 2990.009 18 82 300 0.003 18 82 301 0.002 14 86 302 0.042 16 84 303 0.046 2080 304 0.002 13 87 305 0.002 15 85 306 0.008 16 84 307 0.006 16 84 3080.044 23 77 309 0.056 38 62 310 0.15 27 73 311 0.31 22 78 312 0.37 56 44313 0.085 30 70 314 2.56 66 34 315 1.02 47 53 316 0.061 17 83 317 0.03120 80 318 0.010 13 87 319 0.004 21 78 320 0.018 21 78 321 0.067 22 78322 0.031 14 86 323 0.004 17 83 324 0.108 28 72 325 0.047 18 82 3260.049 13 87 327 0.653 46 54 328 0.338 48 52 329 0.166 17 83 330 0.041 1882 331 0.073 24 76 332 22 51 49 333 0.068 13 87 334 0.032 15 85 3350.006 12 88 336 12 24 76 337 0.399 17 83 338 0.033 17 83 339 0.715 65 35340 0.862 68 32 341 0.799 70 30 342 0.916 63 37 343 0.495 54 46 344 1.0765 35 345 0.191 27 73 346 0.108 13 87 347 0.378 11 89 348 0.400 14 86349 0.118 14 86 350 0.028 10 90 351 0.047 9 91 352 0.192 10 90 353 9.130 70 354 >25 100 0 355 0.183 18 82 356 0.162 17 83 357 0.124 15 85 3580.128 14 86 359 0.365 11 89 360 >25 76 24 361 >25 100 0 362 0.765 16 84363 0.109 15 85

Example 365: Small Molecule HbF Induction Assay

Cryopreserved primary human CD34⁺ hematopoietic stem and progenitorcells were obtained from AllCells, LLC. The CD34⁺ cells were isolatedfrom the peripheral blood of healthy donors after mobilization byadministration of granulocyte colony-stimulating factor. Cells weredifferentiated ex vivo toward the erythroid lineage using a 2-phaseculture method. In the first phase, cells were cultured in StemSpan™Serum-Free Expansion Media (SFEM) (STEMCELL Technologies Inc.)supplemented with rhSCF (50 ng/mL, Peprotech®, Inc.), rhIL-6 (50 ng/mL,Peprotech®, Inc.), rhIL-3 (50 ng/mL, Peprotech®, Inc.), and rhFlt3L (50ng/mL, Peprotech®, Inc.), and 1× antibiotic-antimycotic (LifeTechnologies, Thermo Fisher Scientific) for 6 days at 37° C. with 5%CO₂. During the second phase, cells were cultured in erythroiddifferentiation media at 5,000 cells/mL in the presence of compound for7 days at 37° C. with 5% CO₂. Erythroid Differentiation Media iscomprised of IMDM (Life Technologies) supplemented with insulin (10μg/mL, Sigma Aldrich), heparin (2 U/mL Sigma Aldrich), holo-transferrin(330 μg/mL, Sigma Aldrich), human serum AB (5%, Sigma Aldrich),hydrocortisone (1 μM, STEMCELL Technologies), rhSCF (100 ng/mL,Peprotech®, Inc.), rhIL-3 (5 ng/mL, Peprotech®, Inc.), rhEPO (3 U/mL,Peprotech®, Inc.), and 1× antibiotic-antimycotic. All compounds weredissolved and diluted into dimethylsulfoxide (DMSO) and were added toculture media for a final concentration of 0.3% DMSO for testing in a7-point, 1:3 dilution series starting at 30 uM.

Staining and Flow Cytometry

For viability analysis, samples were washed and resuspended inphosphate-buffered saline (PBS) and stained with LIVE/DEAD™ FixableViolet Dead Cell Stain Kit (Life Technologies, L34963) for 20 minutes.Cells were then washed again with PBS and resuspended in PBSsupplemented with 2% fetal bovine serum (FBS), and 2 mM EDTA to preparefor cell surface marker analysis. Cells were labeled withallophycocyanin-conjugated CD235a (1:100, BD Biosciences, 551336) andBrilliant Violet-conjugated CD71 (1:100, BD Biosciences, 563767)antibodies for 20 minutes. For analysis of cytoplasmic Fetal Hemoglobin(HbF), cells were fixed and permeabilized using the Fixation(BioLegend®, 420801) and Permeabilization Wash (BioLegend®, 421002)Buffers according to the manufacturer's protocol. During thepermeabilization step, cells were stained with phycoerythrin-conjugatedor FITC-conjugated HbF-specific antibody (1:10-1:25, Invitrogen™,MHFH04-4) for 30 minutes. Stained cells were washed withphosphate-buffered saline before analysis on the FACSCanto™ II flowcytometer or LSRFortessa™ (BD Biosciences). Data analysis was performedwith FIowJo™ Software (BD Biosciences).

HbF Induction Activity of Compounds (Table 2)

mPB CD34+ cells were expanded for 6 days, then erythroid differentiatedin the presence of compound for 7 days. Cells were fixed, stained andanalyzed by flow cytometry. Table 2 shows HbF induction activity of thecompounds. HbF Amax=the highest percentage of cells staining positivefor HbF (% HbF+ cells) in the fitted dose-response curve. The baseline %HbF+ cells for DMSO-treated cells is approximately 30-40%.

TABLE 2 Cmpd no. HbF EC₅₀ (μM) HbF Amax 17 0.266 80 109 0.129 77 1410.006 90 142 0.038 89 145 0.030 76 156 0.012 81 160 0.999 84 179 0.07479 203 0.045 82 207 0.089 85 210 0.064 86 283 0.127 61 287 0.060 63

Example 366: Cell Culture for shRNA and CRISPR Assays

HEK293T cells were maintained in DMEM high glucose complete media withsodium pyruvate, non-essential amino acids, 10% FBS, 2 mM L-glutamine,100 U/mL pen/strep, 25 mM HEPES. Unless stated otherwise, all reagentsfor culturing HEK293T cells were obtained from Invitrogen™.

Mobilized peripheral blood (mPB) CD34+ cells (AllCells, LLC) weremaintained in StemSpan™ serum-free expansion media (SFEM) (STEMCELLTechnologies Inc.) supplemented with 50 ng/mL each of rhTPO, rhIL-6,rhFLT3L, rhSCF for 2-3 days prior to shRNA transduction or targetedribonucleoprotein (RNP) electroporation targeting WIZ. All cytokineswere obtained from Peprotech®, Inc. Cell cultures were maintained at 37°C. and 5% CO₂ in a humidified tissue culture incubator.

Generation of shRNA Lentiviral Clones Targeting WIZ

5-phosphorylated sense and anti-sense complementary single-stranded DNAoligos of the respective shRNA against WIZ were synthesized byIntegrated DNA Technologies, Inc. (IDT). Each DNA oligonucleotide wasdesigned with PmeI/AscI restriction overhangs on 5′- and 3′-ends,respectively, for subsequent compatible ligation into the lentiviralvector backbone. Equimolar of each of the complementary oligonucleotideswere annealed in NEB Buffer 2 (New England Biolabs® Inc.) by heating ona heating block at 98° C. for 5 minutes followed by cooling to roomtemperature on the bench top. Annealed double-stranded DNAoligonucleotides were ligated into pHAGE lentiviral backbone digestedwith PmeI/AscI using T4 DNA ligase kit (New England Biolabs). Ligationreactions were transformed into chemically competent Stbl3 cells(Invitrogen™) according to the manufacturer's protocol. Positive cloneswere verified using the sequencing primer (5′-ctacattttacatgatagg-3′;SEQ ID NO: 2) and plasmids were purified by Alta Biotech LLC.

Lentivirus particles for the respective shRNA constructs were generatedby co-transfection of HEK293T cells with pCMV-dR8.91 and pCMV-VSV-Gexpressing envelope plasmid using Lipofectamine 3000 reagent in 150 mmtissue culture dish format as per manufacturer's instructions(Invitrogen™). Lentivirus supernatant was harvested 48 hours afterco-transfection, filtered through a 0.45 μm filter (Millipore) andconcentrated using Amicon Ultra 15 with Ultracel-100 membrane(Millipore). Infectious units of each of the lentivirus particle wasdetermined by flow cytometry using eGFP expression as marker oftransduction after serial dilution and infection of HEK293T cells.

The shRNA sequences are as follows:

(SEQ ID NO: 3) shWIZ_#1 5′-AGCCCACAATGCCACGGAAAT-3′; (SEQ ID NO: 4)shWIZ_#2 5′-GCAACATCTACACCCTCAAAT-3′; (SEQ ID NO: 5)shWIZ_#4 5′-TGACCGAGTGGTACGTCAATG-3′; (SEQ ID NO: 6)shWIZ_#5 5′-AGCGGCAGAACATCAACAAAT-3′.Lentiviral shRNA Transduction and FACS of mPB CD34+ Cells

mPB CD34+ transduction was performed on retronectin coated non-tissueculture treated 96 well-flat bottom plates (Corning, Inc.). Briefly,plates were coated with 100 μL of RetroNectin® (1 μg/mL) (TAKARABIO,Inc.), sealed and incubated at 4° C. overnight. RetroNectin® was thenremoved and plates were incubated with BSA (bovine serum albumin) (1%)in PBS for 30 minutes at room temperature. Subsequently, BSA (bovineserum albumin) was aspirated and replaced with 100 μL of lentiviralconcentrate and centrifuged at 2000×g for 2 hours at room temperature.Next, residual supernatant was gently pipetted out and ready fortransductions of mPB CD34+ cells. Ten thousand cells were plated in 150μL of StemSpan™ Serum-free Expansion Medium (SFEM) supplemented with 50ng/mL each of rhTPO, rhIL-6, rhFLT3L, rhSCF to initiate transduction.Cells were cultured for 72 hours prior to assessing transductionefficiencies using eGFP expression as a marker.

eGFP-positive cells were sorted on an FACSAria™ III (BD Biosciences).Briefly, the transduced mPB CD34+ cell population was washed andre-suspended with FACS buffer containing 1× Hank's buffered salinesolution, EDTA (1 mM) and FBS (2%). Sorted eGFP-positive cells were usedfor the erythroid differentiation assay.

Targeting CRISPR Knockout of WIZ

Alt-R CRISPR-Cas9 crRNA and tracrRNA(5′-AGCAUAGCAAGUUAAAAUAAGGCUAGUCCGUUAUCAACUUGAAAAAGUGGCACCGAGUCGGUGCUUU-3′; SEQ ID NO: 7) were purchased from Integrated DNATechnologies, Inc. Equimolar tracrRNA was annealed with WIZ targetingcrRNA (Table 3) in Tris buffer (10 mM, pH 7.5) by heating at 95° C. for5 minutes using a polymerase chain reaction (PCR) machine (Bio-Rad)followed by cooling to room temperature on the benchtop. Subsequently, aribonucleoprotein (RNP) complex was generated by mixing annealedtracrRNA:crRNA with 6 ug of Cas9 at 37° C. for 5 minutes in 1× buffercontaining HEPES (100 mM), KCl (50 mM), MgCl₂ (2.5 mM), glycerol(0.03%), DTT (1 mM) and Tris pH 7.5 (2 mM).

Electroporation of the RNP complex was performed on a 4D-Nucleofector™(Lonza) as per manufacturer's recommendation. Briefly, 50,000 mPB CD34+cells resuspended in Primary Cell P3 Buffer with supplement (Lonza) werepre-mixed with 5 μL of RNP complex per well in nucleocuvettes andincubated for 5 minutes at room temperature. Subsequently, the mixturewas electroporated using the CM-137 program. Cells were cultured for 72hours post-RNP electroporation before initiating erythroiddifferentiation. The crRNA sequences are shown in Table 3 below.

TABLE 3 SEQ Name Sequence (5′ to 3′) Target genomic region Strand ID NOrg_0111 ACGGAGGCTAAGCGTCGCAA random guide, non- 8 targeting WIZ_6AACATCTTTCGGGCCGTAGG chr19: 15427143- (+) 9 15427163 WIZ_9GACATCCGCTGCGAGTTCTG chr19: 15427488- (−) 10 15427510 WIZ_12TGCAGCGTCCCGGGCAGAGC chr19: 15425751- (−) 11 15425773 WIZ_14CAAGCCGTGCCTCATCAAGA chr19: 15425571- (−) 12 15425593 WIZ_15CGGGCACACCTGCGGCAGTT chr19: 15424942- (−) 13 15424964 WIZ_18AGTGGGTGCGGCACTTACAG chr19: 15423169- (−) 14 15423191Erythroid Differentiation of shRNA Transduced or RNP Electroporated mPBCD34+ Cells

Erythroid differentiation was initiated by plating 8,000RNP-electroporated or FACS sorted eGFP+ mPB CD34+ cells per well in96-well tissue culture plate. Base differentiation media consists ofIMDM (Iscove's Modified Dulbecco's Medium), human AB serum (5%),transferrin (330 μg/mL), Insulin (10 μg/mL) and Heparin (2 IU/mL).Differentiation media was supplemented with rhSCF (100 ng/mL), rhIL-3(10 ng/mL), rhEPO (2.5 U/mL) and hydrocortisone (1 μM). After 4 days ofdifferentiation, the cells were split (1:4) in fresh media to maintainoptimal growth density. Cells were cultured for additional 3 days andutilized for assessment of fetal hemoglobin (HbF) expression.

Analysis of HbF Gene Expression by RNA-seq

Two independent, targeted CRISPR/Cas9 knockout (KO) of WIZ was doneusing WIZ_6 and WIZ_18 gRNAs or a non-targeting scrambled gRNA negativecontrol in mPB CD34+ HSCs. Cells from KO and negative control were thencultured for 7 days for erythroid differentiation and used for total RNAisolation (Zymo Research, catalogue #R1053). The quality of isolated RNAwas determined before sequencing using Agilent RNA 6000 Pico Kit(Agilent, catalogue #5067-1513). RNA sequencing libraries were preparedusing the Illumina TruSeq Stranded mRNA Sample Prep protocol andsequenced using the Illumina NovaSeq6000 platform (Illumina). Sampleswere sequenced to a length of 2×76 base-pairs. For each sample, salmonversion 0.8.2 (Patro et al. 2017; doi: 10.1038/nmeth.4197) was used tomap sequenced fragments to annotated transcripts in the human referencegenome hg38 provided by the ENSEMBL database. Per-gene expression levelswere obtained by summing the counts of transcript-level counts usingtximport (Soneson et al. 2015; doi: 10.12688/f1000research.7563.1).DESeq2 was used to normalize for library size and transcript lengthdifferences, and to test for differential expression between samplestreated with the gRNAs targeting WIZ and the samples treated with thescrambled gRNA controls (Love et al. 2014; doi:10.1186/s13059-014-0550-8). Data were visualized using ggplot2 (WickhamH (2016). ggplot2: Elegant Graphics for Data Analysis. Springer-VerlagNew York. ISBN 978-3-319-24277-4; https://ggplot2.tidyverse.org).

HbF Intracellular Staining

One hundred thousand cells were aliquoted into U-bottom 96-well plateand stained for 20 min in the dark with diluted LIVE/DEAD fixable violetviability dye as per manufacturer's recommendation (Invitrogen). Cellswere washed with FACS staining buffer and subsequently stained withanti-CD71-BV711 (BD Biosciences) and anti-CD235a-APC (BD Biosciences)for 20 mins in the dark. After two rounds of washes with three volumesof 1×PBS, cells were fixed and permeabilized with 1×BD Cytofix/Cytoperm(BD Biosciences) for 30 minutes at room temperature in the dark.Subsequently, cells were washed twice with three volumes of 1× Perm/washbuffer (BD Biosciences). Anti-HbF-FITC (ThermoScientific) was diluted(1:25) in 1× perm/wash buffer, added to permeablized cells and incubatedfor 30 minutes at room temperature in the dark. Next, cells were washedtwice with three volumes of 1× perm/wash buffer and analyzed by flowcytometry using LSR Fortessa (BD Biosciences). Data was analyzed withFlowJo software.

Results WIZ KO Upregulates HBG1/2 Expression Upon ErythroidDifferentiation

Targeted KO of WIZ using two independent gRNAs (WIZ_6 and WIZ_18)demonstrated upregulation of fetal hemoglobin genes (HBG1/2), aspresented in FIG. 1A.

Loss of WIZ Induces Fetal Hemoglobin Expression in mPB CD34⁺ DerivedErythroid Cells

In order to validate whether WIZ is a negative regulator of HbFexpression, shRNA and CRISPR-Cas9-mediated knockdown and knockoutfunctional genetics approaches were employed. mPB CD34⁺ cells weretreated with shRNA or CRISPR-Cas9 reagents and erythroid differentiatedfor 7 days prior to flow cytometry analysis. Targeted knockdown of WIZtranscript results in 78-91% HbF⁺ cells compared to 40% for the negativecontrol scrambled shRNA. Error bars represent standard error of twobiological replicates with three technical replicates each (FIG. 1B).CRISPR/Cas9-mediated targeted loss of WIZ results in 62-88% HbF⁺ cellscompared to 39% for random guide crRNA. Error bars represent standarderror of one biological sample with four technical replicates (FIG. 1C).To summarize, the results indicate that loss of WIZ induces HbF in humanprimary erythroid cells. As such, the zinc finger transcription factorWidely Interspaced Zinc Finger Motifs (WIZ) was identified as a noveltarget for HbF induction. These data provide genetic evidence that WIZis a regulator of fetal hemoglobin expression and represents a noveltarget for the treatment of sickle cell disease and beta-thalassemia.

Having thus described several aspects of several embodiments, it is tobe appreciated various alterations, modifications, and improvements willreadily occur to those skilled in the art. Such alterations,modifications, and improvements are intended to be part of thisdisclosure, and are intended to be within the spirit and scope of thedisclosure. Accordingly, the foregoing description and drawings are byway of example only.

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

1. A compound of Formula (I″), or a pharmaceutically acceptable saltthereof, wherein:

is a single bond or a double bond; X is selected from CH, CF, and N;R^(x) is selected from hydrogen, C₁-C₆alkyl, halo, C₁-C₆alkoxyl, andC₃-C₈cycloalkyl; R′ is selected from hydrogen and C₁-C₆alkyl; R¹ isselected from hydrogen and C₁-C₆alkyl; each R² is independently selectedfrom C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and oxo, wherein the C₁-C₆alkylis substituted with 0-1 occurrence of R^(2a); or 2 R² on non-adjacentcarbon atoms together with the non-adjacent carbon atoms to which theyare attached form a bridging ring; R^(2a) is selected from C₁-C₆alkoxyland hydroxyl; R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl,—SO₂R⁴, C₁-C₆haloalkyl, —C(═O)—O—(R⁵), —C(═O)—(R⁶), C₃-C₁₀cycloalkyl,and a 4- to 10-membered heterocyclyl comprising 1-2 heteroatomsindependently selected from N, O and S, wherein the C₁-C₈alkyl andC₁-C₆haloalkyl are each independently substituted with 0-3 occurrencesof R^(3a), and wherein the C₃-C₁₀cycloalkyl and 4- to 10-memberedheterocyclyl are each independently substituted with 0-3 occurrences ofR^(3b); or R³ together with the nitrogen atom to which it is attachedand R² together with the carbon atom to which it is attached form a 5-or 6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N, O and S, which 5- or 6-membered heterocyclyl is substituted with0-2 occurrences of an oxo group; each R^(3a) is independently selectedfrom C₃-C₁₀cycloalkyl, a 4- to 10-membered heterocyclyl comprising 1-2heteroatoms independently selected from N, O and S, a 5- to 10-memberedheteroaryl comprising 1-4 heteroatoms independently selected from N, O,and S, C₆-C₁₀aryl, C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein theC₃-C₁₀cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-memberedheteroaryl and C₆-C₁₀aryl are substituted with 0-4 occurrences ofR^(3b); each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl; R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, C₆-C₁₀aryl, and —NR^(4b)R^(4c), wherein theC₁-C₆alkyl is substituted with 0-1 occurrence of R^(4a); R^(4a) isselected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl; R^(4b) isselected from hydrogen, and C₁-C₆alkyl; R^(4c) is selected fromhydrogen, C₁-C₆alkyl, and C₃-C₈cycloalkyl; R⁵ is selected fromC₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl; R⁶ is selected fromC₁-C₆alkyl, C₃-C₈cycloalkyl, C₆-C₁₀aryl, a 4- to 10-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and and —NR^(4b)R^(4c) wherein the C₁-C₆alkyl is substituted with0-1 occurrence of R^(6a), the C₃-C₈cycloalkyl is substituted with 0-1occurrence of R^(6b), and the 4- to 10-membered heterocyclyl issubstituted with 0-1 occurrence of C₁-C₆alkyl; R^(6a) is selected fromC₆-C₁₀aryl and C₃-C₈cycloalkyl; R^(6b) is selected from halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, and C₁-C₆alkyl; R⁷ is selected fromhydrogen and C₁-C₆alkyl; R⁸ is selected from hydrogen and C₁-C₆alkyl; orR⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S; n is 0, 1, 2, 3 or 4; m is 0, 1 or2; and p is 0 or
 1. 2. (canceled)
 3. The compound of claim 1 having aFormula (I′), or a pharmaceutically acceptable salt thereof, wherein:

is a single bond or a double bond; X is selected from CH, CF, and N; R′is selected from hydrogen and C₁-C₆alkyl; R¹ is selected from hydrogenand C₁-C₆alkyl; each R² is independently selected from C₁-C₆alkyl,C₁-C₆haloalkyl, halo, and oxo, wherein the C₁-C₆alkyl is substitutedwith 0-1 occurrence of R^(2a); or 2 R² on non-adjacent carbon atomstogether with the non-adjacent carbon atoms to which they are attachedform a bridging ring; R^(2a) is selected from C₁-C₆alkoxyl and hydroxyl;R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴,C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and —C(═O)—(R⁶), wherein the C₁-C₈alkyland C₁-C₆haloalkyl are independently substituted with 0-3 occurrences ofR^(3a); or R³ together with the nitrogen atom to which it is attachedand R² together with the carbon atom to which it is attached form a 5-or 6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N, O and S; each R^(3a) is independently selected fromC₃-C₁₀cycloalkyl, a 4- to 6-membered heterocyclyl comprising 1-2heteroatoms independently selected from N, O and S, a 5- to 10-memberedheteroaryl comprising 1-4 heteroatoms independently selected from N, O,and S, C₆-C₁₀aryl, C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein theC₃-C₁₀cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-memberedheteroaryl and C₆-C₁₀aryl are substituted with 0-4 occurrences ofR^(3b); each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl; R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl issubstituted with 0-1 occurrence of R^(4a); R^(4a) is selected fromC₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl; R⁵ is selected fromC₁-C₆alkyl C₃-C₈cycloalkyl, and C₆-C₁₀aryl; R⁶ is selected fromC₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl issubstituted with 0-1 occurrence of R^(6a) and the C₃-C₈cycloalkyl issubstituted with 0-1 occurrence of R^(6b); R^(6a) is selected fromC₆-C₁₀aryl and C₃-C₈cycloalkyl; R^(6b) is selected from halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, and C₁-C₆alkyl; R⁷ is selected fromhydrogen and C₁-C₆alkyl; R⁸ is selected from hydrogen and C₁-C₆alkyl; orR⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S; n is 0, 1, 2, 3 or 4; m is 0, 1 or2; and p is 0 or
 1. 4. The compound of claim 1 having a Formula (I), ora pharmaceutically acceptable salt, wherein:

X is selected from CH, CF, and N; R′ is selected from hydrogen andC₁-C₆alkyl; R¹ is selected from hydrogen and C₁-C₆alkyl; each R² isindependently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and oxo,wherein the C₁-C₆alkyl is substituted with 0-1 occurrence of R^(2a); or2 R² on non-adjacent carbon atoms together with the non-adjacent carbonatoms to which they are attached form a bridging ring; R^(2a) isselected from C₁-C₆alkoxyl and hydroxyl; R³ is selected from hydrogen,C₁-C₈alkyl, C₂-C₆alkenyl, —SO₂R⁴, C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and—C(═O)—(R⁶), wherein the C₁-C₈alkyl and C₁-C₆haloalkyl are independentlysubstituted with 0-3 occurrences of R^(3a); or R³ together with thenitrogen atom to which it is attached and R² together with the carbonatom to which it is attached form a 5- or 6-membered heterocyclylcomprising 0-1 additional heteroatom selected from N, O and S; eachR^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, a 5- to 10-membered heteroaryl comprising 1-4heteroatoms independently selected from N, O, and S, C₆-C₁₀aryl,C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein the C₃-C₁₀cycloalkyl,4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl andC₆-C₁₀aryl are substituted with 0-4 occurrences of R^(3b); each R^(3b)is independently selected from C₁-C₆alkoxyl, halo, C₁-C₆haloalkyl,C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴, and hydroxyl; R⁴is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-memberedheterocyclyl comprising 1-2 heteroatoms independently selected from N, Oand S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substituted with 0-1occurrence of R^(4a); R^(4a) is selected from C₃-C₈cycloalkyl,C₆-C₁₀aryl, and C₁-C₆alkoxyl; R⁵ is selected from C₁-C₆alkylC₃-C₈cycloalkyl, and C₆-C₁₀aryl; R⁶ is selected from C₁-C₆alkyl,C₃-C₈cycloalkyl, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl is substitutedwith 0-1 occurrence of R^(6a) and the C₃-C₈cycloalkyl is substitutedwith 0-1 occurrence of R^(6b); R^(6a) is selected from C₆-C₁₀aryl andC₃-C₈cycloalkyl; R^(6b) is selected from halo, C₁-C₆haloalkyl,C₁-C₆haloalkoxyl, and C₁-C₆alkyl; R⁷ is selected from hydrogen andC₁-C₆alkyl; R⁸ is selected from hydrogen and C₁-C₆alkyl; or R⁷ and R⁸together with the nitrogen atom to which they are attached form a 5- or6-membered heterocyclyl comprising 0-1 additional heteroatom selectedfrom N, O, and S; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1.5. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein X is selected from CH, CF, and N; R′ is selected fromhydrogen and C₁-C₃alkyl; R¹ is selected from hydrogen and C₁-C₃alkyl;each R² is independently selected from unsubstituted C₁-C₆alkyl,C₁-C₆haloalkyl and halo; or 2 R² on non-adjacent carbon atoms togetherwith the non-adjacent carbon atoms to which they are attached form abridging ring; R³ is selected from hydrogen, C₁-C₈alkyl, C₂-C₆alkenyl,—SO₂R⁴, C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and —C(═O)—(R⁶), wherein theC₁-C₈alkyl and C₁-C₆haloalkyl are independently substituted with 0-3occurrences of R^(3a); or R³ together with the nitrogen atom to which itis attached and R² together with the carbon atom to which it is attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N and 0; each R^(3a) is independently selectedfrom C₃-C₁₀cycloalkyl, a 4- to 6-membered heterocyclyl comprising 1-2heteroatoms independently selected from N, O and S, a 5- to 10-memberedheteroaryl comprising 1-4 heteroatoms independently selected from N, O,and S, C₆-C₁₀aryl, C₁-C₆alkoxyl, hydroxyl, and —C(═O)—NR⁷R⁸, wherein theC₃-C₁₀cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-memberedheteroaryl and C₆-C₁₀aryl are substituted with 0-4 occurrences ofR^(3b); each R^(3b) is independently selected from C₁-C₆alkoxyl, halo,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl, —CN, —SO₂NR⁷R⁸, —SO₂R⁴,and hydroxyl; R⁴ is selected from C₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to6-membered heterocyclyl comprising 1-2 heteroatoms independentlyselected from N, O and S, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl issubstituted with 0-1 occurrence of R^(4a); R^(4a) is selected fromC₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl; R⁵ is selected fromC₁-C₆alkyl C₃-C₈cycloalkyl, and C₆-C₁₀aryl; R⁶ is selected fromC₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, wherein the C₁-C₆alkyl issubstituted with 0-1 occurrence of R^(6a) and the C₃-C₈cycloalkyl issubstituted with 0-1 occurrence of R^(6b); R^(6a) is selected fromC₆-C₁₀aryl and C₃-C₈cycloalkyl; R^(6b) is selected from chloro, fluoro,C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, and C₁-C₆alkyl; R⁷ is selected fromhydrogen and C₁-C₆alkyl; R⁸ is selected from hydrogen and C₁-C₆alkyl; orR⁷ and R⁸ together with the nitrogen atom to which they are attachedform a 5- or 6-membered heterocyclyl comprising 0-1 additionalheteroatom selected from N, O, and S; n is 0, 1, 2 or 3; m is 0, 1 or 2;and p is 0 or
 1. 6. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X is selected from CH and N; R′ isselected from hydrogen and methyl; R¹ is selected from hydrogen andmethyl; each R² is independently selected from unsubstituted C₁-C₆alkyland halo; or 2 R² on non-adjacent carbon atoms together with thenon-adjacent carbon atoms to which they are attached form aC₁-C₃alkylene bridging ring; R³ is selected from hydrogen, C₁-C₈alkyl,C₂-C₆alkenyl, —SO₂R⁴, C₁-C₆haloalkyl, —C(═O)—O—(R⁵) and —C(═O)—(R⁶),wherein the C₁-C₈alkyl and C₁-C₆haloalkyl are independently substitutedwith 0-3 occurrences of R^(3a); or R³ together with the nitrogen atom towhich it is attached and R² together with the carbon atom to which it isattached form a 5- or 6-membered heterocyclyl comprising 0-1 additionalO heteroatom; each R^(3a) is independently selected fromC₃-C₁₀cycloalkyl, a 4- to 6-membered heterocyclyl comprising 1-2heteroatoms independently selected from N, O and S, a 5- to 10-memberedheteroaryl comprising 1-4 heteroatoms independently selected from N, O,and S and phenyl, wherein the C₃-C₁₀cycloalkyl, 4- to 6-memberedheterocyclyl, 5- to 10-membered heteroaryl and phenyl are substitutedwith 0-4 occurrences of R^(3b); each R^(3b) is independently selectedfrom C₁-C₆alkoxyl, halo, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, C₁-C₆alkyl,—CN, —SO₂NR⁷R⁸, —SO₂R⁴, and hydroxyl; R⁴ is selected fromC₃-C₈cycloalkyl, C₁-C₆alkyl, a 4- to 6-membered heterocyclyl comprising1-2 heteroatoms independently selected from N, O and S, and C₆-C₁₀aryl,wherein the C₁-C₆alkyl is substituted with 1 occurrence of R^(4a);R^(4a) is selected from C₃-C₈cycloalkyl, C₆-C₁₀aryl, and C₁-C₆alkoxyl;R⁵ is selected from C₁-C₆alkyl C₃-C₆cycloalkyl, and C₆-C₁₀aryl; R⁶ isselected from C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₆-C₁₀aryl, wherein theC₁-C₆alkyl is substituted with 0-1 occurrence of R^(6a) and theC₃-C₈cycloalkyl is substituted with 0-1 occurrence of R^(6b); R^(6a) isselected from C₆-C₁₀aryl and C₃-C₈cycloalkyl; R^(6b) is selected fromchloro, fluoro, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl, and C₁-C₆alkyl; R⁷ isselected from hydrogen and C₁-C₆alkyl; R⁸ is selected from hydrogen andC₁-C₆alkyl; or R⁷ and R⁸ together with the nitrogen atom to which theyare attached form a 5- or 6-membered heterocyclyl comprising 0-1additional heteroatom selected from N, O, and S; n is 0, 1, 2 or 3; m is0, 1 or 2; and p is 0 or
 1. 7. (canceled)
 8. (canceled)
 9. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein X isselected from CH and N; R′ is hydrogen; R¹ is hydrogen; each R² isindependently selected from unsubstituted C₁-C₃alkyl; R³ is selectedfrom C₁-C₆alkyl, C₂-C₆alkenyl, —SO₂R⁴ and unsubstituted C₁-C₆haloalkyl,wherein the C₁-C₆alkyl is substituted with 0-2 occurrences of R^(3a);each R^(3a) is independently selected from C₃-C₁₀cycloalkyl, a 4- to6-membered heterocyclyl comprising 1 O heteroatom, a 6-memberedheteroaryl comprising 1-2 N heteroatoms and phenyl, wherein theC₃-C₁₀cycloalkyl, 4- to 6-membered heterocyclyl, 6-membered heteroaryland phenyl are substituted with 0-2 occurrences of R^(3b); each R^(3b)is independently selected from chloro, fluoro, C₁-C₆haloalkyl,C₁-C₆haloalkoxyl and C₁-C₆alkyl; R⁴ is selected from C₃-C₈cycloalkyl,C₁-C₆alkyl, a 4- to 6-membered heterocyclyl comprising 1 O heteroatomand phenyl, wherein the C₁-C₆alkyl is substituted with 1 occurrence ofR^(4a); R^(4a) is selected from C₃-C₈cycloalkyl and phenyl; n is 0, 1 or2; m is 1 or 2; and p is
 1. 10. (canceled)
 11. The compound of claim 1,or a pharmaceutically acceptable salt thereof, having a Formula (Ia):

12-22. (canceled)
 23. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R³ is selected from methyl, ethyl,n-propyl, i-propyl, 2-propanyl, butyl, i-butyl, 2-butanyl,3-methyl-2-butanyl, i-pentyl, 3-pentanyl, neopentyl,2,4-dimethylpentanyl, and —CH₂—(CH₂)₀₋₁—R^(3a).
 24. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein R^(3a)is C₃-C₁₀cycloalkyl, wherein the C₃-C₁₀cycloalkyl is substituted with0-4 occurrences of R^(3b), wherein each R^(3b) is independently selectedfrom C₁-C₆alkoxyl, chloro, fluoro, C₁-C₆haloalkyl, C₁-C₆haloalkoxyl andC₁-C₆alkyl.
 25. (canceled)
 26. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(3a) is selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantanyl,

27-31. (canceled)
 32. The compound of claim 1, wherein

is a single bond.
 33. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, selected from:

1-(5-((1-(((1s,4s)-4- methoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(5-fluoro-2-methylbenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((1r,4r)-4- methoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

methyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-acetylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(4-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclopentylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

phenyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((1-((tetrahydro-2H-pyran-4- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-isobutyl-8- azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclopentylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(thiazol-2-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((4,4- difluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S,5S)-4-isobutyl-3,5-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-((tetrahydro-2H-pyran-4- yl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(cyclopropylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-ethyl-4-((tetrahydro-2H-pyran-4- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-oxo-2-(piperidin-1-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(2-cyclohexylethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isobutyrylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-fluoro-1-isobutylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1- ((cyclohexylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-chlorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1- ((cyclopropylmethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2-methylbenzyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclopentylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-(pyridin-3-ylmethyl)-8- azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((tetrahydro-2H-pyran-3- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(4-fluorobenzyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclohexylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(pyridin-2-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-((4,4- difluorocyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(2-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-(tetrahydro-2H-pyran-4- yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclobutylmethyl)-4- fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,4S)-4- methoxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((3-ethyl-4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-(2-fluoro-2-methylpropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1s,4R)-4- methoxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-(3-methylbenzyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cycloheptylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(thiazol-4-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4S)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclohexylmethyl)-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-(cyclohexylmethyl)-3- (methoxymethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methylbutyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(3-fluorobenzyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclohexylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2,2,2-trifluoroethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(R)-1-(5-((4-isobutyl-3- (methoxymethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexanecarbonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((2-methyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclopentylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-(pyridin-3-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(heptan-4-yl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-hydroxy-2- (hydroxymethyl)propyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclobutylethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((1-methyl-1H-pyrazol-5- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((1-((tetrahydrofuran-3- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((3,3-dimethyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isopentyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(isopropylsulfonyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclopentylethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-((3,3-difluorocyclobutyl)methyl)-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(R)-1-(5-((1-((tetrahydrofuran-3- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclobutylmethyl)-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-((4,4- difluorocyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

tert-butyl 4-((3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((1-(isopropylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(3,3,3-trifluoro-2,2- dimethylpropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-((3,3-difluorocyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

isobutyl 4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((4-(cycloheptylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-(cyclohexylmethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(((1r,4r)-4- methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,4R)-5-(cyclohexylmethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(pyridin-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((1- (trifluoromethyl)cyclopropyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isobutylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2,2,3,3-tetrafluoropropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclobutylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-((3,3- difluorocyclobutyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

cyclohexyl 4-((3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-carboxylate

1-(5-((1-(oxetan-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((1-methyl-1H-imidazol-4- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((tetrahydrofuran-3- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-isobutyl-3,3-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((tetrahydro-2H-pyran-4- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-phenylpropanoyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclobutylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(thiazol-4-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isopentylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(1-(pyridin-3-yl)ethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclobutylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-((1-methyl-1H-imidazol-4-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-(((1s,4s)-4- methoxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(pyridin-4-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((3,3- difluorocyclobutyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((1r,4r)-4- ethoxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,4R)-5-(pyridin-3-ylmethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclopentylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(sec-butylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(piperidin-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-benzoylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S)-2-methyl-4-((tetrahydrofuran-2- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2-cyclohexylethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(1-(trifluoromethyl)cyclopropane-1-carbonyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-((tetrahydro-2H-pyran-3- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-cyclohexylpropanoyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-isobutylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-(pyridin-3-ylmethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(pentan-3-yl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((3-methyl-4-(pyridin-3-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-neopentylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1S,4S)-5-(isopropylsulfonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(isobutylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-(3-fluorobenzyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S,5R)-3,5-dimethyl-4-((tetrahydro-2H-pyran-4-yl)methyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((3-(difluoromethyl)-4-isobutylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(2-(tetrahydro-2H- pyran-4-yl)ethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2-cyclohexylethyl)-3-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((1- fluorocyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclohexylmethyl)-3-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(1-(pyridin-3-yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1S,4S)-5-(pyridin-3-ylmethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(benzylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1S,4S)-5-(cyclohexylmethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclobutylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-isopropylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methyl-1-(tetrahydro-2H-pyran-4- yl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-(cyclohexylmethyl)-3- (difluoromethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-fluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,4R)-5-(isopropylsulfonyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-isobutyl-2-oxopiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(4-fluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-isopropyl-4-((tetrahydro-2H- pyran-4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(methylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(cyclohexylmethyl)-2-oxopiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((l-ethylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((3-methyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-((tetrahydrofuran-3- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((3r,5r,7r)-adamantan-1-yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(3-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cycloheptylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(1-phenylethyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclobutylpropan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3- (trifluoromethoxy)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-4-(((2R,6S)-2,6- dimethyltetrahydro-2H-pyran-4-yl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-propylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cycloheptylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-phenethylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((2-methyl-4-((tetrahydro-2H-pyran- 4-yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-3-methyl-4-((tetrahydrofuran-2- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(pyridin-4-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S,5R)-4-isobutyl-3,5-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(1-(1-isobutylpiperidin-4- yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-benzylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-benzyl-4-fluoropiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,2,3,3-tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(1-(5-(((2S,4R)-1-((3,3- difluorocyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(phenylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(((3r,5r,7r)-adamantan-1- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((5-fluoropyridin-3- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4R)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methoxyethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3,3,3-trifluoro-2,2- dimethylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,4-dimethylpentan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4S)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((5-methylpyridin-3- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4S)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((1R,5S)-8-((cyclohexylmethyl)-8- azabicyclo[3.2.1]octan-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-3-methyl-4-((tetrahydrofuran-2- yl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isopropylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5((4-(cyclohexylmethyl)-3,3- dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(2-fluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4S)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-fluoro-2-methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4S)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((tetrahydrofuran-2- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((hexahydropyrazino[2,1c][1,4]oxazin-8(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-(cyclopropylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4R)-1-(cyclohexylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(R)-1-(5-((4-(cyclohexylmethyl)-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(3-methoxybenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methylbenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,4S)-4- hydroxycyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(3-fluoro-2-methylbenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5- a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,2-difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4S)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(1-(3,5-difluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4S)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(3,4-difluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-methylbutan-2-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(pentan-3-yl)piperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(3-methylbutan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((6-methylpyridin-3- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-((4,4- dimethylcyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(4-methylbenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2R,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((3S,5S)-4-(cyclohexylmethyl)-3,5-dimethylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-(2-(4,4-difluorocyclohexyl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5- a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexylmethyl)piperidin-4-yl)methyl)-4-methylpyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- dimethylcyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-benzylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(pyridin-3-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(cyclohexylmethyl)-4- fluoropiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(((1r,4r)-4- hydroxycyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,4S)-4- methoxycyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(2-methyla]lyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1,4-diazepan-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(2-hydroxy-2- methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-isobutyl-1,4-diazepan-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((octahydro-2H-pyrido[1,2- a]pyrazin-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-(cyclohexylmethyl)-1,4-diazepan-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(1-(3-fluorophenyl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(azetidin-3-ylmethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-((1-methyl-1H-pyrazol-5- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isobutylazetidin-3- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2-(tetrahydro-2H-pyran-4- yl)propan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexylmethyl)azetidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-methylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexylmethyl)pyrrolidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,4-difluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(pyridin-3-ylmethyl)pyrrolidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-isobutyl-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclobutylmethyl)pyrrolidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-fluoro-5- (trifluoromethyl)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(3-fluorobenzyl)pyrrolidin-3-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-(1H-imidazol-4- yl)ethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-isobutylpyrrolidin-3- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-cyclohexyl-2,2- difluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((3R,4S)-3,4- difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((4-isopropylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-isobutyl-2,2-dimethylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(((1r,4r)-4- hydroxycyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2,3-difluorobenzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(isopropylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(R)-1-(5-((4-(cyclohexylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-(2-hydroxy-2- methylpropyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(2,2,3,3- tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-((6-(trifluoromethyl)pyridin-3- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1s,3R)-3- methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-((3-methyloxetan-3- yl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1s,3R)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-((1- (trifluoromethyl)cyclopropyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((1s,3s)-3- methoxycyclobutyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(2-methoxy-2- methylpropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,3S)-3- methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-2-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,3S)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(4- (trifluoromethoxy)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((3R,4S)-3,4- difluorocyclopentyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(4-(trifluoromethyl)benzyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-4-(((3R,4S)-3,4- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((9aR)-octahydro-2H-quinolizin-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(isopropylsulfonyl)-2-methylpiperazin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-((tetrahydro-2H-pyran-4-yl)sulfonyl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(2,2,3,3- tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,3S)-3- methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1s,3R)-3- methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,3S)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((1s,3R)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((R)-3,3- difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((S)-3,3- difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((R)-3,3- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((S)-3,3- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,3R,4S)-3,4- difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,3R,4S)-3,4- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(azepan-4-ylmethyl)pyrazolo[1,5- a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

tert-butyl 4-((3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)azepane-1-carboxylate

1-(5-((1-methylazepan-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(cyclohexylmethyl)azepan-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(2,2,3,3- tetrafluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(2,2-difluoroethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(2,2,2- trifluoroethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(3,3,3- trifluoropropyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(oxetan-2-ylmethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(2,2-difluoro-3- methoxypropyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5- a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-cyclobutyl-2- methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-(oxetan-3-yl)piperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-cyclobutylpiperidin-4- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1- (methylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(isopropylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclopropylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-isobutyryl-2- methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclobutanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(1- methylpiperidine-4-carbonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(pyrrolidin-1- ylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(2S,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N,N,2-trimethylpiperidine-1- sulfonamide

(2S,4R)-N-cyclopentyl-4-((3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2- methylpiperidine-1-sulfonamide

(2S,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N,N,2-trimethylpiperidine-1- carboxamide

1-(5-(((2S,4R)-2-methyl-1-(pyrrolidine-1-carbonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(2S,4R)-N-cyclopentyl-4-((3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-2- methylpiperidine-1-carboxamide

1-(5-((1-(pyrrolidin-1-ylsulfonyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

N-cyclopentyl-4-((3-(2,4- dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5- yl)methyl)piperidine-1-sulfonamide

(2S,4R)-4-((3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-5-yl)methyl)-N-ethyl-N,2-dimethylpiperidine-1- carboxamide

1-(5-((1-(((1s,3s)-3- methoxycyclobutyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((1-(((1r,3R,4S)-3,4- difluorocyclopentyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,3S)-3- methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1s,3R)-3- methoxycyclobutyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((1r,3R,4S)-3,4- difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-2-methyl-1-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((R)-3,3- difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(((S)-3,3- difluorocyclopentyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4S)-1-((4,4- difluorocyclohexyl)methyl)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-4-fluoro-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4S)-4-fluoro-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-4-fluoro-2-methyl-1-(oxetan-3-yl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-((1-isobutyl-2- (trifluoromethyl)piperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(R)-1-(5-((4-oxohexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((1,1-dioxidohexahydro-5H- isothiazolo[2,3-a]pyrazin-5-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,3S)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((1s,3R)-3- methoxycyclobutyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((1r,3R,4S)-3,4- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((R)-3,3- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(((S)-4-(((S)-3,3- difluorocyclopentyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-((1- methylcyclobutyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((S)-3-methyl-4-(((1r,4S)-4-(trifluoromethyl)cyclohexyl)methyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-(((3S)-3-methyl-4-(oxetan-2-ylmethyl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-((2-oxaspiro[3.3]heptan-6- yl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-((6,6-difluorospiro[3.3]heptan-2-yl)methyl)-3-methylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(2,2-difluoroethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-(2,2-difluoro-3-methoxypropyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-cyclobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(oxetan-3-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(2-oxaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-cyclohexyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(4,4-difluorocyclohexyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(spiro[3.3]heptan-2-yl)piperazin-1-yl)methyl)pyrazolo[1,5- a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(2-methyl-2- azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((3-methyl-4-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)piperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((4-cyclohexylpiperazin-1- yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(ethylsulfonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclohexanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-(((4-(cyclopentanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclobutanecarbonyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine- 2,4(1H,3H)-dione

1-(5-(1-(4-isobutylpiperazin-1- yl)ethyl)pyrazolo[1,5-a]pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

1-(5-((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclopropylmethyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine- 2,4(1H,3H)-dione

5-fluoro-1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-fluoropyrimidine- 2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine- 2,4(1H,3H)-dione

5-chloro-1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-((4,4- difluorocyclohexyl)methyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methoxypyrimidine- 2,4(1H,3H)-dione

5-cyclopropyl-1-(5-(((2S,4R)-1-isobutyl-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(cyclopropanecarbonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

1-(5-(((2S,4R)-1-(ethylsulfonyl)-2-methylpiperidin-4-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3- yl)pyrimidine-2,4(1H,3H)-dione

(S)-5-fluoro-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methoxypyrimidine-2,4(1H,3H)-dione

(S)-5-cyclopropyl-1-(5-((4-isobutyl-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione

(S)-1-(5-((4-(cyclopropylmethyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)-5-methylpyrimidine- 2,4(1H,3H)-dione

(S)-1-(5-((4-((4,4- difluorocyclohexyl)methyl)-3-methylpiperazin-1-yl)methyl)pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione


34. (canceled)
 35. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.
 36. (canceled)
 37. A method of treatingor preventing a disease or disorder in a subject in need thereof, themethod comprising administering to the subject a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 38. A method of treating or preventing adisorder that is affected by the reduction or modulation of WIZ proteinlevels, in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof.39-41. (canceled)
 42. A method of inhibiting, reducing, or eliminatingthe activity of WIZ protein or WIZ protein expression, the methodcomprising administering to the subject a compound of claim 1, or apharmaceutically acceptable salt thereof.
 43. A method of inducing orpromoting fetal hemoglobin in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 44. A method of reactivating fetal hemoglobin production orexpression in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 45.A method of increasing fetal hemoglobin expression in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 46. A method of treating ahemoglobinopathy in a subject in need thereof, the method comprisingadministering to the subject a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 47.A method of treating sickle cell disease in a subject in need thereof,the method comprising administering to the subject a therapeuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 48. A method of treating beta-thalassemia in asubject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound of claim 1, ora pharmaceutically acceptable salt thereof. 49-75. (canceled)
 76. Apharmaceutical combination comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and one or more additionaltherapeutic agent(s).
 77. A compound of formula (X-1) or a salt thereof,

wherein:

is a single bond or a double bond; X is selected from CH, CF, and N; Zis selected from hydrogen and 2,4-dimethoxybenzyl (DMB); R^(x) isselected from hydrogen, C₁-C₆alkyl, halo, C₁-C₆alkoxyl, andC₃-C₈cycloalkyl; R^(N) is selected from hydrogen and a nitrogenprotecting group PG; R′ is selected from hydrogen and C₁-C₆alkyl; R¹ isselected from hydrogen and C₁-C₆alkyl; each R² is independently selectedfrom C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and oxo, wherein the C₁-C₆alkylis substituted with 0-1 occurrence of R^(2a); or 2 R² on non-adjacentcarbon atoms together with the non-adjacent carbon atoms to which theyare attached form a bridging ring; R^(2a) is selected from C₁-C₆alkoxyland hydroxyl; n is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and p is 0 or 1.